Compounds for the treatment of Hepatitis C

ABSTRACT

The invention encompasses compounds of formula I as well as compositions and methods of using the compounds. The compounds have activity against hepatitis C virus (HCV) and are useful in treating those infected with HCV.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/989,472 filed Nov. 21, 2007.

BACKGROUND OF THE INVENTION

Hepatitis C virus (HCV) is a major human pathogen, infecting anestimated 170 million persons worldwide—roughly five times the numberinfected by human immunodeficiency virus type 1. A substantial fractionof these HCV infected individuals develop serious progressive liverdisease, including cirrhosis and hepatocellular carcinoma (Lauer, G. M.;Walker, B. D. N. Engl. J. Med. 2001, 345, 41-52).

HCV is a positive-stranded RNA virus. Based on a comparison of thededuced amino acid sequence and the extensive similarity in the5′-untranslated region, HCV has been classified as a separate genus inthe Flaviviridae family. All members of the Flaviviridae family haveenveloped virions that contain a positive stranded RNA genome encodingall known virus-specific proteins via translation of a single,uninterrupted, open reading frame.

Considerable heterogeneity is found within the nucleotide and encodedamino acid sequence throughout the HCV genome. At least six majorgenotypes have been characterized, and more than 50 subtypes have beendescribed. The major genotypes of HCV differ in their distributionworldwide, and the clinical significance of the genetic heterogeneity ofHCV remains elusive despite numerous studies of the possible effect ofgenotypes on pathogenesis and therapy.

The single strand HCV RNA genome is approximately 9500 nucleotides inlength and has a single open reading frame (ORF) encoding a single largepolyprotein of about 3000 amino acids. In infected cells, thispolyprotein is cleaved at multiple sites by cellular and viral proteasesto produce the structural and non-structural (NS) proteins. In the caseof HCV, the generation of mature non-structural proteins (NS2, NS3,NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. Thefirst one is believed to be a metalloprotease and cleaves at the NS2-NS3junction; the second one is a serine protease contained within theN-terminal region of NS3 (also referred to as NS3 protease) and mediatesall the subsequent cleavages downstream of NS3, both in cis, at theNS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B,NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiplefunctions, acting as a cofactor for the NS3 protease and possiblyassisting in the membrane localization of NS3 and other viral replicasecomponents. The complex formation of the NS3 protein with NS4A seemsnecessary to the processing events, enhancing the proteolytic efficiencyat all of the sites. The NS3 protein also exhibits nucleosidetriphosphatase and RNA helicase activities. NS5B (also referred to asHCV polymerase) is a RNA-dependent RNA polymerase that is involved inthe replication of HCV. The HCV NS5B protein is described in “StructuralAnalysis of the Hepatitis C Virus RNA Polymerase in Complex withRibonucleotides (Bressanelli; S. et al., Journal of Virology 2002,3482-3492; and Defrancesco and Rice, Clinics in Liver Disease 2003, 7,211-242.

Currently, the most effective HCV therapy employs a combination ofalpha-interferon and ribavirin, leading to sustained efficacy in 40% ofpatients (Poynard, T. et al. Lancet 1998, 352, 1426-1432). Recentclinical results demonstrate that pegylated alpha-interferon is superiorto unmodified alpha-interferon as monotherapy (Zeuzem, S. et al. N.Engl. J. Med. 2000, 343, 1666-1672). However, even with experimentaltherapeutic regimens involving combinations of pegylatedalpha-interferon and ribavirin, a substantial fraction of patients donot have a sustained reduction in viral load. Thus, there is a clear andimportant need to develop effective therapeutics for treatment of HCVinfection.

DESCRIPTION OF THE INVENTION

One aspect of the invention is a compound of formula I

where:R¹ is CO₂R⁵ or CONR⁶R⁷;R² is a -5,5-, -5,6-, -5,7-, -6,6-, -6,7-, or -7,7-spirocyclic diamineattached to the carbonyl through one nitrogen and substituted with 0-3R⁸ substituents;R³ is hydrogen, halo, alkyl, alkenyl, hydroxy, benzyloxy, or alkoxy;R⁴ is cycloalkyl;R⁵ is hydrogen or alkyl;R⁶ is hydrogen, alkyl, alkylSO₂, cycloalkylSO₂, haloalkylSO₂,(R⁹)(R¹⁰)NSO₂, or (R¹¹)SO₂;R⁷ is hydrogen or alkyl;R⁸ is oxo, hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl,alkylcarbonyl, (cycloalkyl)carbonyl, alkoxycarbonyl, aminocarbonyl,(alkylamino)carbonyl, (dialkylamino)carbonyl, (R¹²)carbonyl, benzyl, orbenzyloxycarbonyl;R⁹ is hydrogen or alkyl;R¹⁰ is hydrogen or alkyl;R¹¹ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,N-(alkyl)piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, orhomomorpholinyl; andR¹² is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,N-(alkyl)piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, orhomomorpholinyl;or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R¹ isCONR⁶R⁷; R⁶ is alkylSO₂, cycloalkylSO₂, haloalkylSO₂, (R⁹)(R¹⁰)NSO₂, or(R¹¹)SO₂; and R⁷ is hydrogen.

Another aspect of the invention is a compound of formula I where R³ ishydrogen.

Another aspect of the invention is a compound of formula I where R³ ismethoxy.

Another aspect of the invention is a compound of formula I where R⁴ iscyclohexyl.

Another aspect of the invention is a compound of formula I where R⁶ is(R⁹)(R¹⁰)NSO₂ or (R¹¹)SO₂.

Another aspect of the invention is a compound of formula I according tothe following stereochemistry.

Another aspect of the invention is a compound of formula I according tothe following stereochemistry.

Any scope of any variable, including R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, and R¹² can be used independently with the scope of any otherinstance of a variable.

Unless specified otherwise, these terms have the following meanings.“Alkyl” means a straight or branched alkyl group composed of 1 to 6carbons. “Alkenyl” means a straight or branched alkyl group composed of2 to 6 carbons with at least one double bond. “Cycloalkyl” means amonocyclic ring system composed of 3 to 7 carbons. “Hydroxyalkyl,”“alkoxy” and other terms with a substituted alkyl moiety includestraight and branched isomers composed of 1 to 6 carbon atoms for thealkyl moiety. “Haloalkyl” and “haloalkoxy” include all halogenatedisomers from monohalo substituted alkyl to perhalo substituted alkyl.“Aryl” includes carbocyclic and heterocyclic aromatic substituents.Parenthetic and multiparenthetic terms are intended to clarify bondingrelationships to those skilled in the art. For example, a term such as((R)alkyl) means an alkyl substituent further substituted with thesubstituent R.

The ring systems shown below illustrate the size and skeletal nature ofthe -5,5-, -5,6-, -5,7-, -6,6-, -6,7-, and -7,7-spirocyclic diaminemoieties.

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, and zinc.

Some of the compounds of the invention possess asymmetric carbon atoms(see, for example, the compound below). The invention includes allstereoisomeric forms, including enantiomers and diastereomers as well asmixtures of stereoisomers such as racemates. Some stereoisomers can bemade using methods known in the art. Stereoisomeric mixtures of thecompounds and related intermediates can be separated into individualisomers according to methods commonly known in the art. The use ofwedges or hashes in the depictions of molecular structures in thefollowing schemes and tables is intended only to indicate relativestereochemistry, and should not be interpreted as implying absolutestereochemical assignments.

Synthetic Methods

The compounds may be made by methods known in the art including thosedescribed below. Some reagents and intermediates are known in the art.Other reagents and intermediates can be made by methods known in the artusing readily available materials. The variables (e.g. numbered “R”substituents) used to describe the synthesis of the compounds areintended only to illustrate how to make and are not to be confused withvariables used in the claims or in other sections of the specification.Abbreviations used within the schemes generally follow conventions usedin the art.

Methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate can be hydrolyzed to2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (See Scheme 1). Thiscompound can be condensed with a variety of sulfonyl ureas, using forexample, 1,1′-carbonyldiimidazole in combination with1,8-diazabicyclo[5.4.0]undec-7-ene in anhydrous THF. The resultant acylsulfamides can be subjected to known coupling reactions with a diversityof 2-formyl boronic acids or esters, using for example, Suzuki couplingconditions, to provide cyclic hemiaminal intermediates of the typedepicted. These compounds can be converted to indolobenzazepinesderivatives by treatment with methyl 2-(dimethoxyphosphoryl)acrylateunder the influence of cesium carbonate in DMF via consecutive Michaeland Horner Emmons reactions.

Related fused cyclopropyl ester derivatives can be generated by methodsknown in the art, including treatment of the indolobenzazepine esterswith trimethyl sulfoxonium iodide under strongly basic conditions inDMSO. The residual aliphatic ester moiety in the resultant fusedcyclopropanes can be hydrolyzed and the product acids can be condensedwith a variety of alkyl-fused diamines. For example,O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborateand diisopropyl ethyl amine in DMSO can give alkyl fused diaminecarboxamides.

N-protected diamines can also be coupled to the intermediateindolobenzazepine acids and the resultant diamine carboxamides can bedeprotected using methods known in the art and derivatized using avariety of synthetic protocols, some illustrative examples of which areshown below (See Scheme 2).

An intermediate useful for the synthesis of some compounds of theinvention involves the preparation of the tert-butyl esterindolobenzazepine shown in Scheme 3.

This methodology involves base catalyzed hydrolysis of the indole methylester shown, followed by its reaction with either thionyl chloride andpotassium tertiary butoxide, or alkylation with silver carbonate andtertiary butyl bromides. The resultant compound can be transformed usingchemistry analogous to that outlined previously to provide the mixedester indolobenzazepines shown above.

These intermediates are useful in an alternative procedure that can beemployed for the preparation of acylsulfamide and acylsulfonamidealkyl-fused diamines, as shown in Scheme 4. Cyclopropanation of anintermediate t-butyl ester indolobenzazepine and subsequent cleavage ofthe t-butyl ester group can generate the acid which can be coupled to adiversity of sulfonamides and sulfonylureas. Subsequent hydrolysisaffords the related aliphatic acid, which can be coupled with adiversity of alkyl-fused diamines. For example,O-(1H-benzotriazol-1-yl)-N,N, N′,N′-tetramethyluronium tetrafluoroborateand diisopropyl ethyl amine in DMSO can give the alkyl fused diaminecarboxamides.

Some examples exist as stereoisomeric mixtures. The inventionencompasses all stereoisomers of the compounds. Methods of fractionatingstereoisomeric mixtures are well known in the art, and include but arenot limited to; preparative chiral supercritical fluid chromatography(SFC) and chiral high performance liquid chromatography (HPLC). Anexample using this approach is shown in scheme 5.

An additional method to achieve such separations involves thepreparation of mixtures of diastereomers which can be separated using avariety of methods known in the art. One example of this approach isshown below (Scheme 6).

Some diastereomeric amides can be separated using reverse phase HPLC.After hydroysis, the resultant optically active acids can be coupledwith fused diamine derivatives (Scheme 6). For example,O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborateand diisopropyl ethyl amine in DMSO can be used to give the alkyl fusedcarboxamides. Other standard acid amine coupling methods can also beused to give optically active carboxamides.

Biological Methods

The compounds demonstrated activity against HCV NS5B as determined inthe following HCV RdRp assays.

HCV NS5B RdRp cloning, expression, and purification. The cDNA encodingthe NS5B protein of HCV, genotype 1b, was cloned into the pET21aexpression vector. The protein was expressed with an 18 amino acidC-terminal truncation to enhance the solubility. The E. coli competentcell line BL21(DE3) was used for expression of the protein. Cultureswere grown at 37° C. for ˜4 hours until the cultures reached an opticaldensity of 2.0 at 600 nm. The cultures were cooled to 20° C. and inducedwith 1 mM IPTG. Fresh ampicillin was added to a final concentration of50 μg/ml and the cells were grown overnight at 20° C.

Cell pellets (3 L) were lysed for purification to yield 15-24 mgs ofpurified NS5B. The lysis buffer consisted of 20 mM Tris-HCl, pH 7.4, 500mM NaCl, 0.5% triton X-100, 1 mM DTT, 1 mM EDTA, 20% glycerol, 0.5 mg/mllysozyme, 10 mM MgCl2, 15 ug/ml deoxyribonuclease I, and Complete TMprotease inhibitor tablets (Roche). After addition of the lysis buffer,frozen cell pellets were resuspended using a tissue homogenizer. Toreduce the viscosity of the sample, aliquots of the lysate weresonicated on ice using a microtip attached to a Branson sonicator. Thesonicated lysate was centrifuged at 100,000×g for 1 hr at 4° C. andfiltered through a 0.2 μm filter unit (Corning).

The protein was purified using two sequential chromatography steps:Heparin sepharose CL-6B and polyU sepharose 4B (Pharmacia). Thechromatography buffers were identical to the lysis buffer but containedno lysozyme, deoxyribonuclease I, MgCl2 or protease inhibitor and theNaCl concentration of the buffer was adjusted according to therequirements for charging the protein onto the column. Each column waseluted with a NaCl gradient which varied in length from 5-50 columnvolumes depending on the column type. After the final chromatographystep, the resulting purity of the enzyme is >90% based on SDS-PAGEanalysis. The enzyme was aliquoted and stored at −80° C.

Standard HCV NS5B RdRp enzyme assay. HCV RdRp genotype 1b assays wererun in a final volume of 60 μl in 96 well plates (Corning 3600). Theassay buffer is composed of 20 mM Hepes, pH 7.5, 2.5 mM KCl, 2.5 mMMgCl2, 1 mM DTT, 1.6 U RNAse inhibitor (Promega N2515), 0.01 mg/ml BSA(Sigma B6917), and 2% glycerol. All compounds were serially diluted(3-fold) in DMSO and diluted further in water such that the finalconcentration of DMSO in the assay was 2%. HCV RdRp genotype 1b enzymewas used at a final concentration of 28 nM. A polyA template was used at6 nM, and a biotinylated oligo-dT12 primer was used at 180 nM finalconcentration. Template was obtained commercially (Amersham 27-4110).Biotinylated primer was prepared by Sigma Genosys. 3H-UTP was used at0.6 μCi (0.29 μM total UTP). Reactions were initiated by the addition ofenzyme, incubated at 30° C. for 60 min, and stopped by adding 25 μl of50 mM EDTA containing SPA beads (4 μg/μl, Amersham RPNQ 0007). Plateswere read on a Packard Top Count NXT after >1 hr incubation at roomtemperature.

Modified HCV NS5B RdRp enzyme assay. A modified enzyme assay wasperformed essentially as described for the standard enzyme assay exceptfor the following: The biotinylated oligo dT12 primer was precaptured onstreptavidin-coated SPA beads by mixing primer and beads in assay bufferand incubating at room temperature for one hour. Unbound primer wasremoved after centrifugation. The primer-bound beads were resuspended in20 mM Hepes buffer, pH 7.5 and used in the assay at final concentrationsof 20 nM primer and 0.67 μg/μl beads. Order of addition in the assay:enzyme (1.75 nM) was added to diluted compound followed by the additionof a mixture of template (0.36 nM), 3H-UTP (0.6 μCi, 0.29 μM), andprimer-bound beads, to initiate the reaction; concentrations given arefinal. Reactions were allowed to proceed for 4 hours at 30° C.

IC₅₀ values for compounds were determined using seven different [I].IC₅₀ values were calculated from the inhibition using the formulay=A+((B−A)/(1+((C/x)^D))).

FRET Assay Preparation. The HCV FRET screening assay was performed in96-well cell culture plates. The FRET peptide (Anaspec, Inc.) (Talianiet al., Anal. Biochem. 1996, 240, 60-67) contains a fluorescence donor,EDANS, near one end of the peptide and an acceptor, DABCYL, near theother end. The fluorescence of the peptide is quenched by intermolecularresonance energy transfer (RET) between the donor and the acceptor, butas the NS3 protease cleaves the peptide the products are released fromRET quenching and the fluorescence of the donor becomes apparent. Theassay reagent was made as follows: 5× cell Luciferase cell culture lysisreagent from Promega (#E153A) diluted to 1× with dH₂O, NaCl added to 150mM final, the FRET peptide diluted to 20 μM final from a 2 mM stock.

To prepare plates, HCV replicon cells, with or without a Renillaluciferase reporter gene, were trypsinized and plated in a 96-well platewith titrated test compounds added in columns 3 through 12; columns 1and 2 contained a control compound (HCV control inhibitor), and thebottom row contained cells with DMSO only. The plates were then placedin a CO₂ incubator at 37° C.

Assays. Subsequent to addition of the test compounds described above(FRET Assay Preparation), at various times the plate was removed andAlamar blue solution (Trek Diagnostics, #00-100) was added to measurecellular toxicity. After reading in a Cytoflour 4000 instrument (PEBiosystems), plates were rinsed with PBS and then used for FRET assay bythe addition of 30 ul of the FRET peptide assay reagent described above(FRET Assay Preparation) per well. The plate was then placed into theCytoflour 4000 instrument which had been set to 340 excite/490 emission,automatic mode for up to 20 cycles and the plate read in a kinetic mode.Typically, the signal to noise using an endpoint analysis after thereads was at least three-fold. Alternatively, after Alamar blue reading,plates were rinsed with PBS, then used for luciferase assay using thePromega Dual-Glo Luciferase Assay System or the Promega EnduRen LiveCell Substrate assay.

Compound analysis was performed by quantification of the relative HCVreplicon inhibition and the relative cytotoxicity values. To calculatecytoxicity values, the average Alamar Blue fluorescence signals from thecontrol wells were set as 100% non-toxic. The individual signals in eachof the compound test wells were then divided by the average controlsignal and multiplied by 100% to determine percent cytotoxicity. Tocalculate the HCV replicon inhibition values, an average backgroundvalue was obtained from the two wells containing the highest amount ofHCV control inhibitor at the end of the assay period. These numbers weresimilar to those obtained from naïve Huh-7 cells. The background numberswere then subtracted from the average signal obtained from the controlwells and this number was used as 100% activity. The individual signalsin each of the compound test wells were then divided by the averagedcontrol values after background subtraction and multiplied by 100% todetermine percent activity. EC₅₀ values were calculated as theconcentration which caused a 50% reduction in FRET or luciferaseactivity. The two numbers generated for the compound plate, percentcytoxicity and percent activity, were used to determine compounds ofinterest for further analysis.

Representative data for compounds are reported in Table 1.

TABLE 1 Structure IC₅₀ EC₅₀

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

A > 0.5 μM; B 0.00458 μM-0.5 μM; C < 0.02 μM but an exact value was notdetermined; D > 0.04 μM but an exact value was not determined; D < 0.07μM but an exact value was not determined; IC₅₀ values were determinedusing the preincubation protocol. EC50 values were determined using theFRET assay.

Pharmaceutical Compositions and Methods of Treatment

The compounds demonstrate activity against HCV NS5B and can be useful intreating HCV and HCV infection. Therefore, another aspect of theinvention is a composition comprising a compound, or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier.

Another aspect of the invention is a composition further comprising acompound having anti-HCV activity.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is an interferon. Another aspect of theinvention is where the interferon is selected from interferon alpha 2B,pegylated interferon alpha, consensus interferon, interferon alpha 2A,and lymphoblastoid interferon tau.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is a cyclosporin. Another aspect of theinvention is where the cyclosporin is cyclosporin A.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is selected from the group consisting ofinterleukin 2, interleukin 6, interleukin 12, a compound that enhancesthe development of a type 1 helper T cell response, interfering RNA,anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospatedehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is effective to inhibit the function of atarget selected from HCV metalloprotease, HCV serine protease, HCVpolymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCVegress, HCV NS5A protein, IMPDH, and a nucleoside analog for thetreatment of an HCV infection.

Another aspect of the invention is a composition comprising a compound,or a pharmaceutically acceptable salt thereof, a pharmaceuticallyacceptable carrier, an interferon and ribavirin.

Another aspect of the invention is a method of inhibiting the functionof the HCV replicon comprising contacting the HCV replicon with acompound or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of inhibiting the functionof the HCV NS5B protein comprising contacting the HCV NS5B protein witha compound or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of treating an HCV infectionin a patient comprising administering to the patient a therapeuticallyeffective amount of a compound or a pharmaceutically acceptable solvateor salt thereof. In another embodiment the compound is effective toinhibit the function of the HCV replicon. In another embodiment thecompound is effective to inhibit the function of the HCV NS5B protein.

Another aspect of the invention is a method of treating an HCV infectionin a patient comprising administering to the patient a therapeuticallyeffective amount of a compound, or a pharmaceutically acceptable solvateor salt thereof, in conjunction with (prior to, after, or concurrently)another compound having anti-HCV activity.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is an interferon.

Another aspect of the invention is the method where the interferon isselected from interferon alpha 2B, pegylated interferon alpha, consensusinterferon, interferon alpha 2A, and lymphoblastoid interferon tau.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is a cyclosporin.

Another aspect of the invention is the method where the cyclosporin iscyclosporin A.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is selected from interleukin 2, interleukin 6,interleukin 12, a compound that enhances the development of a type 1helper T cell response, interfering RNA, anti-sense RNA, Imiqimod,ribavirin, an inosine 5′-monophospate dehydrogenase inhibitor,amantadine, and rimantadine.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is effective to inhibit the function of atarget selected from the group consisting of HCV metalloprotease, HCVserine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCVentry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and anucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is effective to inhibit the function of targetin the HCV life cycle other than the HCV NS5B protein.

“Therapeutically effective” means the amount of agent required toprovide a meaningful patient benefit as understood by practitioners inthe field of hepatitis and HCV infection.

“Patient” means a person infected with the HCV virus and suitable fortherapy as understood by practitioners in the field of hepatitis and HCVinfection.

“Treatment,” “therapy,” “regimen,” “HCV infection,” and related termsare used as understood by practitioners in the field of hepatitis andHCV infection.

The compounds of this invention are generally given as pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound or its pharmaceutically acceptable salt and a pharmaceuticallyacceptable carrier and may contain conventional excipients. Atherapeutically effective amount is that which is needed to provide ameaningful patient benefit. Pharmaceutically acceptable carriers arethose conventionally known carriers having acceptable safety profiles.Compositions encompass all common solid and liquid forms includingcapsules, tablets, losenges, and powders as well as liquid suspensions,syrups, elixers, and solutions. Compositions are made using commonformulation techniques, and conventional excipients (such as binding andwetting agents) and vehicles (such as water and alcohols) are generallyused for compositions.

Solid compositions are normally formulated in dosage units andcompositions providing from about 1 to 1000 mg of the active ingredientper dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be presentin a unit range similar to agents of that class used clinically.Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, theliquid composition will be in a unit dosage range of 1-100 mg/mL. Someexamples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100mg/mL. Generally, other agents will be present in a unit range similarto agents of that class used clinically. Typically, this is 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oraland parenteral methods are preferred. Generally, the dosing regimen willbe similar to other agents used clinically. Typically, the daily dosewill be 1-100 mg/kg body weight daily. Generally, more compound isrequired orally and less parenterally. The specific dosing regime,however, will be determined by a physician using sound medicaljudgement.

The invention also encompasses methods where the compound is given incombination therapy. That is, the compound can be used in conjunctionwith, but separately from, other agents useful in treating hepatitis andHCV infection. In these combination methods, the compound will generallybe given in a daily dose of 1-100 mg/kg body weight daily in conjunctionwith other agents. The other agents generally will be given in theamounts used therapeutically. The specific dosing regime, however, willbe determined by a physician using sound medical judgement.

Some examples of compounds suitable for compositions and methods arelisted in Table 2.

TABLE 2 Type of Inhibitor or Brand Name Target Source Company Omega IFNIFN-ω Intarcia Therapeutics BILN-2061 serine protease BoehringerIngelheim inhibitor Pharma KG, Ingelheim, Germany Summetrel antiviralEndo Pharmaceuticals Holdings Inc., Chadds Ford, PA Roferon A IFN-α2a F.Hoffmann-La Roche LTD, Basel, Switzerland Pegasys PEGylated IFN-α2a F.Hoffmann-La Roche LTD, Basel, Switzerland Pegasys and PEGylated IFN- F.Hoffmann-La Roche Ribavirin α2a/ribavirin LTD, Basel, SwitzerlandCellCept HCV IgG F. Hoffmann-La Roche immunosuppressant LTD, Basel,Switzerland Wellferon lymphoblastoid IFN- GlaxoSmithKline plc, αn1Uxbridge, UK Albuferon - α albumin IFN-α2b Human Genome Sciences Inc.,Rockville, MD Levovirin ribavirin ICN Pharmaceuticals, Costa Mesa, CAIDN-6556 caspase inhibitor Idun Pharmaceuticals Inc., San Diego, CAIP-501 antifibrotic Indevus Pharmaceuticals Inc., Lexington, MAActimmune INF-γ InterMune Inc., Brisbane, CA Infergen A IFN alfacon-1InterMune Pharmaceuticals Inc., Brisbane, CA ISIS 14803 antisense ISISPharmaceuticals Inc, Carlsbad, CA/Elan Phamaceuticals Inc., New York, NYJTK-003 RdRp inhibitor Japan Tobacco Inc., Tokyo, Japan Pegasys andPEGylated IFN-α2a/ Maxim Pharmaceuticals Ceplene immune modulator Inc.,San Diego, CA Ceplene immune modulator Maxim Pharmaceuticals Inc., SanDiego, CA Civacir HCV IgG Nabi immunosuppressant BiopharmaceuticalsInc., Boca Raton, FL Intron A and IFN-α2b/α1- RegeneRx Zadaxin thymosinBiopharmiceuticals Inc., Bethesda, MD/ SciClone Pharmaceuticals Inc, SanMateo, CA Levovirin IMPDH inhibitor Ribapharm Inc., Costa Mesa, CAViramidine Ribavirin Prodrug Ribapharm Inc., Costa Mesa, CA Heptazymeribozyme Ribozyme Pharmaceuticals Inc., Boulder, CO Intron A IFN-α2bSchering-Plough Corporation, Kenilworth, NJ PEG-Intron PEGylated IFN-α2bSchering-Plough Corporation, Kenilworth, NJ Rebetron IFN-α2b/ribavirinSchering-Plough Corporation, Kenilworth, NJ Ribavirin ribavirinSchering-Plough Corporation, Kenilworth, NJ PEG-Intron/ PEGylated IFN-Schering-Plough Ribavirin α2b/ribavirin Corporation, Kenilworth, NJZadazim Immune modulator SciClone Pharmaceuticals Inc., San Mateo, CARebif IFN-β1a Serono, Geneva, Switzerland IFN-β and IFN-β and EMZ701Transition Therapeutics EMZ701 Inc., Ontario, Canada Batabulin (T67)β-tubulin inhibitor Tularik Inc., South San Francisco, CA MerimepodibIMPDH inhibitor Vertex Pharmaceuticals (VX-497) Inc., Cambridge, MATelaprevir NS3 serine protease Vertex Pharmaceuticals (VX-950, inhibitorInc., Cambridge, MA/ LY-570310) Eli Lilly and Co. Inc., Indianapolis, INOmniferon natural IFN-α Viragen Inc., Plantation, FL XTL-6865 monoclonalantibody XTL (XTL-002) Biopharmaceuticals Ltd., Rehovot, Isreal HCV-796NS5B Replicase Wyeth/Viropharma Inhibitor NM-283 NS5B ReplicaseIdenix/Novartis Inhibitor GL-59728 NS5B Replicase Gene Labs/NovartisInhibitor GL-60667 NS5B Replicase Gene Labs/Novartis Inhibitor 2′C MeANS5B Replicase Gilead Inhibitor PSI 6130 NS5B Replicase Roche InhibitorR1626 NS5B Replicase Roche Inhibitor SCH 503034 serine protease ScheringPlough inhibitor NIM811 Cyclophilin Inhibitor Novartis Suvus Methyleneblue Bioenvision Multiferon Long lasting IFN Viragen/Valentis ActilonTLR9 agonist Coley (CPG10101) Interferon-β Interferon-β-1a SeronoZadaxin Immunomodulator Sciclone Pyrazolopyrimidine HCV Inhibitors ArrowTherapeutics Ltd. compounds and salts From WO- 2005047288 26 May 20052′C Methyl NS5B Replicase Merck adenosine Inhibitor GS-9132 (ACH-806)HCV Inhibitor Achillion/Gilead

DESCRIPTION OF SPECIFIC EMBODIMENTS

Unless otherwise specified, analytical LCMS data on the followingintermediates and examples were acquired using the following columns andconditions. Stop time: Gradient time+1 minute; Starting conc: 0% Bunless otherwise noted; Eluent A: 5% CH₃CN/95% H₂O with 10 mM NH₄OAc(for columns A, D and E); 10% MeOH/90% H₂O with 0.1% TFA (for columns Band C); Eluent B: 95% CH₃CN/5% H₂O with 10 mM NH₄OAc (for columns A, Dand E); 90% MeOH/10% H₂O with 0.1% TFA (for columns B and C); Column A:Phenomenex 10μ 4.6×50 mm C18; Column B: Phenomenex C18 10μ 3.0×50 mm;Column C: Phenomenex 4.6×50 mm C18 10μ; Column D: Phenomenex Lina C18 5μ3.0×50 mm; Column E: Phenomenex 5μ 4.6×50 mm C18.

1H-Indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, methyl ester.Freshly recrystallized pyridinium tribromide (recrystallization from hotAcOH (5 mL per 1 g), rinsed with cold AcOH and dried under high vacuumover KOH) was added in portions (over 10 min.) to a stirring solution ofmethyl 3-cyclohexyl-1H-indole-6-carboxylate (60 g, 233 mmol) (preparedusing procedures describe in WO2004/065367) in CHCl₃/THF (1:1, 1.25 L)at 2o C. The reaction solution was stirred at 0-5° C. for 2.5 h, andwashed with sat. aq. NaHSO₃ (1 L), 1 N HCl (1 L) and brine (1 L). Theorganic layer was dried (MgSO₄) and concentrated. The resulting red oilwas diluted with Et₂O and concentrated. The resulting pink solid wasdissolved into Et₂O (200 mL) treated with hexanes (300 mL) and partiallyconcentrated. The solids were collected by filtration and rinsed withhexanes. The mother liquor was concentrated to dryness and the procedurerepeated. The solids were combined to yield 1H-indole-6-carboxylic acid,2-bromo-3-cyclohexyl-, methyl ester (64 g, 190 mmol, 82%) as a fluffypink solid, which was used without further purification. 1HNMR (300 MHz,CDCl₃) δ 8.47 (br s, 1H), 8.03 (d, J=1.4 Hz, 1H), 7.74 (dd, J=1.4, 8.8Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 3.92 (s, 3H), 2.82 (tt, J=3.7, 11.7 Hz,1H), 1.98-1.72 (m, 7H), 1.50-1.27 (m, 3H). 13CNMR (75 MHz, CDCl₃) δ168.2, 135.6, 130.2, 123.1, 120.8, 120.3, 118.7, 112.8, 110.7, 52.1,37.0, 32.2 (2), 27.0 (2), 26.1. LCMS: m/e 334 (M−H)⁻, ret time 3.34 min,column A, 4 minute gradient.

1H-Indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-. A solution of methyl2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (20 g, 60 mmol) and LiOH(3.8 g, 160 mmol) in MeOH/THF/H₂O (1:1:1, 300 mL) was heated at 90° C.for 2 h. The reaction mixture was cooled in an ice/H₂O bath, neutralizedwith 1M HCl (˜160 mL) diluted with H₂O (250 mL) and stirred for 1 h atrt. The precipitates were collected by filtration rinse with H₂O anddried to yield 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-(quant.) which was used without further purification.

An alternative procedure that can by used to provide1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl- is described below:

A solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (117g, 349 mmol) and LiOH.H₂O (26.4 g, 629 mmol) in MeOH/THF/H2O (1:1:1, 1.8L) was heated at reflux for 3 h. The reaction mixture was cooled in anice/H2O bath to ˜2° C., neutralized with 1M HCl (˜650 mL) (added at sucha rate that temperature did not exceed 5° C.), diluted with H2O (1 L)and stirred while warming to ambient temperature. The precipitates werecollected by filtration rinsed with H₂O and dried to yield the mono THFsolvate of 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl- (135.5 g,345 mmol, 99%) as a yellow solid, which was used without furtherpurification. 1HNMR (300 MHz, CDCl₃) δ 11.01 (br s, 1H), 8.77 (s, 1H),8.07 (d, J=1.5 Hz, 1H), 7.82 (dd, J=1.5, 8.8 Hz, 1H), 7.72 (d, J=8.8 Hz,1H), 3.84-3.74 (m, 4H), 2.89 (m, 1H), 1.98-1.72 (m, 11H), 1.50-1.24 (m,3H). 13CNMR (75 MHz, CDCl3) δ 172.7, 135.5, 130.7, 122.3, 120.9 (2),118.8, 113.3, 111.1, 67.9 (2), 37.0, 32.2 (2), 27.0 (2), 26.1, 25.5 (2).LCMS: m/e 320 (M−H)⁻, ret time 2.21 min, column A, 4 minute gradient.

1H-Indole-6-carboxamide,2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-.1,1′-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirredsolution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g,6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO₂ was instantaneousand when it slowed the solution was heated at 50° C. for 1 hr and thencooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was addedfollowed by the dropwise addition of a solution of DBU (1.34 g, 8.8mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture waspartitioned between ethyl acetate and dilute HCl. The ethyl acetatelayer was washed with water followed by brine and dried over Na₂SO₄. Theextract was concentrated to dryness to leave the title product as a paleyellow friable foam, (2.0 g, 74%, >90% purity, estimated from NMR). ¹HNMR (300 MHz, DMSO-D6) δ ppm 1.28-1.49 (m, 3H) 1.59-2.04 (m, 7H)2.74-2.82 (m, 1H) 2.88 (s, 6H) 7.57 (dd, J=8.42, 1.46 Hz, 1H) 7.74 (d,J=8.78 Hz, 1H) 7.91 (s, 1H) 11.71 (s, 1H) 12.08 (s, 1H).

An alternative method for the preparation of 1H-indole-6-carboxamide,2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]- is described below.

To a 1 L four necked round bottom flask equipped with a mechanicalstirrer, a temperature controller, a N2 inlet, and a condenser, underN2, was added 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (102.0 g,0.259 mol) and dry THF (300 mL). After stirring for 10 min, CDI (50.3 g,0.31 mol) was added portion wise. The reaction mixture was then heatedto 50° C. for 2 h. After cooling to 30° C., N,N-dimethylaminosulfonamide(41.7 g, 0.336 mol) was added in one portion followed by addition of DBU(54.1 mL, 0.362 mol) drop wise over a period of 1 h. The reactionmixture was then stirred at rt for 20 h. The solvent was removed invacuo and the residue was partitioned between EtOAc and 1 N HCl (1:1, 2L). The organic layer was separated and the aqueous layer was extractedwith EtOAc (500 mL). The combined organic layers were washed with brine(1.5 L) and dried over MgSO4. The solution was filtered and concentratedin vacuo to give the crude product (111.0 g). The crude product wassuspended in EtOAc (400 mL) at 60° C. To the suspension was addedheptane (2 L) slowly. The resulting suspension was stirred and cooled to0° C. It was then filtered. The filter cake was rinsed with small amountof heptane and house vacuum air dried for 2 days. The product wascollected as a white solid (92.0 g, 83%). ¹H NMR (MeOD, 300 MHz) δ 7.89(s, H), 7.77 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.4 and 1.8 Hz, 1H), 3.01(s, 6H), 2.73-2.95 (m, 1H), 1.81-2.05 (m, 8H), 1.39-1.50 (m, 2H); m/z429 (M+H)+.

1H-Indole-6-carboxamide,3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)-.A mixture of the2-Bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-1H-indole-6-carboxamide(4.28 g, 0.01 mol), 4-methoxy-2-formylphenyl boronic acid (2.7 g, 0.015mol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (41 mg, 0.0001mol), palladium acetate (11.2 mg), and finely ground potassium carbonate(4.24 g, 0.02 mol) in toluene (30 mL) was stirred under reflux and undernitrogen for 30 min, at which time LC/MS analysis showed the reaction tobe complete. The reaction mixture was then diluted with ethyl acetateand water, and then acidified with an excess of dilute HCl. The ethylacetate layer was then collected and washed with dilute HCl, water andbrine. The organic solution was then dried (magnesium sulfate), filteredand concentrated to give a gum. The gum was diluted with hexanes (250ml) and ethyl acetate (25 mL), and the mixture was stirred for 20 hr at22° C. during which time the product was transformed into a brightyellow granular solid (4.8 g) which was used directly without furtherpurification.

An alternative procedure for the preparation of 1H-indole-6-carboxamide,3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)-is provided below:

To a slurried solution of2-bromo-3-cyclohexyl-N-[(dimethylamino)sulfonyl]-indole-6-carboxamide(54.0 g, 126 mmol), 4-methoxy-2-formylphenylboronic acid (29.5 g, 164mmol) and LiCl (13.3 g, 315 mmol) in EtOH/toluene (1:1, 1 L) was added asolution of Na₂CO₃ (40.1 g, 379 mmol) in water (380 mL). The reactionmixture was stirred 10 min. and then Pd(PPh3)4 (11.3 g, 10.0 mmol) wasadded. The reaction solution was flushed with nitrogen and heated at 70°C. (internal monitoring) overnight and then cooled to rt. The reactionwas diluted with EtOAc (1 L) and EtOH (100 mL), washed carefully with 1Naqueous HCl (1 L) and brine (500 mL), dried (MgSO4), filtered andconcentrated. The residual solids were stirred with Et2O (600 mL) for 1h and collected by filtration to yield 1H-indole-6-carboxamide,3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)-(52.8 g, 109 mmol, 87%) as a yellow powder which was used withoutfurther purification. 1HNMR (300 MHz, d6-DMSO) δ 11.66 (s, 1H), 8.17 (s,1H), 7.75 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (dd, J=1.4,8.4 Hz, 1H), 7.23-7.16 (m, 2H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.54 (d,J=8.8 Hz, 1H), 3.86 (s, 3H), 3.22-3.08 (m, 1H), 2.91 (s, 6H), 2.00-1.74(m, 7H), 1.60-1.38 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 165.7, 158.8,147.2, 139.1, 134.3, 132.0, 123.4, 122.0, 119.2, 118.2, 114.8, 112.3,110.4, 109.8, 79.6, 45.9, 37.2 (2), 34.7, 32.0 (2), 25.9 (2), 24.9.LCMS: m/e 482 (M−H)⁻, ret time 2.56 min, column A, 4 minute gradient.

6H-Isoindolo[2,1-a]indole-3-carboxamide,11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-ethoxy-8-methoxy-. To a 5 Lfour necked round bottom flask equipped with a temperature controller, acondenser, a N2 inlet and a mechanical stirrer, was charged toluene (900mL), EtOH (900 mL),2-bromo-3-cyclohexyl-N—(N,N-dimethylsulfamoyl)-1H-indole-6-carboxamide(90 g, 0.21 mol), 2-formyl-4-methoxyphenylboronic acid (49.2 g, 0.273mol) and LiCl (22.1 g, 0.525 mol). The resulting solution was bubbledwith N₂ for 15 mins. A solution of Na₂CO₃ (66.8 g, 0.63 mol) in H₂O (675mL) was added and the reaction mixture was bubbled with N₂ for another(10 mins). Pd(PPh₃)₄ (7.0 g, 6.3 mmol) was added and the reactionmixture was heated to 70° C. for 20 h. After cooling to 35° C., asolution of 1 N HCl (1.5 L) was added slowly. The resulting mixture wastransferred to a 6 L separatory funnel and extracted with EtOAc (2×1.5L). The combined organic extracts were washed with brine (2 L), driedover MgSO4, filtered and concentrated in vacuo to give a yellow solid,which was triturated with 20% EtOAc in hexane (450 mL, 50° C. to 0° C.)to give3-cyclohexyl-N—(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide(65.9 g) as a yellow solid. HPLC purity, 98%.

The mother liquid from the trituration was concentrated in vacuo. Theresidue was refluxed with EtOH (50 mL) for 3 h. The solution was thencooled to 0° C. The precipitates were filtered and washed with cooledTBME (5° C.) (20 mL). The filter cake was house vacuum air dried to givea further quantity of the title compound as a white solid (16.0 g). HPLCpurity, 99%. ¹H NMR (CDCl₃, 300 MHz) δ 8.75 (s, 1H), 7.96 (s, 1H), 7.73(d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.45 (dd, J=8.4 and 1.4 Hz,1H), 7.09 (d, J=2.2 Hz, 1H), 6.98 (dd, J=8.4 and 2.2 Hz, 1H), 6.50 (s,1H), 3.86 (s, 3H), 3.05 (s, 6H), 2.92-3.13 (m, 3H), 1.85-1.93 (m, 7H),1.40-1.42 (m, 3H), 1.05 (t, J=7.1 Hz, 3H). m/z 512 (M+H)+.

1H-indole-6-carboxamide,3-cyclohexyl-N-[(dimethylamino)sulfonyl]-2-(2-formyl-4-methoxyphenyl)-.11-cyclohexyl-N—(N,N-dimethylsulfamoyl)-6-ethoxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxamidewas dissolved in THF (75 mL). To the solution was added a solution of 2N HCl (300 mL). The mixture was vigorously stirred under N2 at rt for 16h. The resulting suspension was filtered and washed with cooled TBME(2×30 mL). the filer cake was vacuum air dried overnight to give thetitle compound as a yellow solid. HPLC purity, 99% ¹H NMR (DMSO-d6, 300MHz) δ 11.65 (s, 1H), 8.16 (s, 1H), 7.76 (d, J=5.9 Hz, 1H), 7.73 (d,J=5.9 Hz, 1H), 7.58 (dd, J=8.5 and 1.5 Hz, 1H), 7.17-7.20 (m, 2H), 7.08(dd, J=8.5 and 1.4 Hz, 1H), 6.55 (d, J=8.6 Hz, 1H), 3.86 (s, 3H),3.14-3.18 (m, 1H), 2.91 (s, 6H), 1.75-1.99 (m, 7H), 1.48-1.60 (m, 3H);m/z 484 (M+H)+.

7H-Indolo[2,1-a][2]benzazepine-6-carboxylic acid,13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-,methyl ester. A mixture of the3-cyclohexyl-N—(N,N-dimethylsulfamoyl)-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxamide(4.8 g, 0.01 mol), methyl 2-(dimethoxyphosphoryl)acrylate (9.7 g, 0.02mol) and cesium carbonate (7.1 g, 0.02 mol) in DMF (28 mL) was stirredfor 20 hr at an oil bath temperature of 55° C. The mixture was pouredinto ice-water and acidified with dilute HCl to precipitate the crudeproduct. The solid was collected, dried and flash chromatographed onSiO₂ (110 g) using an ethyl acetate and methylene chloride (1:10)solution containing 2% acetic acid. Homogeneous fractions were combinedand evaporated to afford the title compound as a pale yellow solid (3.9g, 71% yield). MS: 552 (M=H+).

An alternate procedure for the preparation of7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid,13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-,methyl ester is provided below.

A solution of11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxamide(cyclic hemiaminal) (63.0 g, 130 mmol), methyl2-(dimethoxyphosphoryl)acrylate (60 g, 261 mmol), cesium carbonate (106g, 326 mmol) in DMF (400 mL) was heated at 60° C. (bath temp) for 4.5 h.Additional methyl 2-(dimethoxyphosphoryl)acrylate (15 g, 65 mmol) andcesium carbonate (21.2 g, 65 mmol) were added and the reaction washeated at 60° C. overnight then and cooled to rt. The stirring reactionmixture was diluted with H₂O (1 L), slowly neutralized with 1N aqueousHCl (800 mL), stirred 3 h, and then the precipitates were collected byfiltration. The solids were triturated with Et2O (800 mL) and dried toyield methyl 7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid,13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-,methyl ester (70.2 g, 127 mmol, 98%) as a yellow solid which was usedwithout further purification. 1HNMR (300 MHz, CDCl3) δ 8.67 (s, 1H),8.09 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.50 (d, J=8.4 Hz,1H), 7.42 (d, J=8.8 Hz, 1H), 7.08 (dd, J=2.6, 8.8 Hz, 1H), 6.98 (d,J=2.6 Hz, 1H), 5.75-5.51 (m, 1H), 4.29-4.01 (m, 1H), 3.89 (s, 3H), 3.82(s, 3H), 3.05 (s, 6H), 2.87-2.73 (m, 1H), 2.11-1.12 (m, 10H). LCMS: m/e550 (M−H)−, ret time 3.21 min, column A, 4 minute gradient.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,methyl ester, (+/−)-. DMSO (5 mL) was added to a mixture oftrimethylsulfoxonium iodide (199 mg, 0.906 mmol) and NaH (38 mg in 60%oil dispersion, 0.953 mmol) in a round-bottomed flask. The reactionmixture was stirred at rt for 0.5 hr.7H-Indolo[2,1-a][2]benzazepine-6-carboxylic acid,13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-(methoxy)-,methyl ester (125 mg, 0.227 mmol) was then added and the reactionmixture was stirred at rt. for 3 hr., and then at 50° C. for a further 3hr. The reaction was then quenched with water and acidified with 1N HClsolution. The crude product then precipitated as a light yellow solidwhich was collected by filtration and air dried, (106 mg, 83% yield). 6mg of this material was then purified by Prep. HPLC to afford the titlecompound as a light yellow solid (1.8 mg). MS m/z 566 (MH⁺), Retentiontime: 3.850 min. ¹H NMR (500 MHz, MeOD) δ ppm 0.28 (m, 0.36H) 1.19-2.20(m, 11.64H) 2.70-3.02 (m, 2H) 3.03 (s, 2.16H) 3.05 (s, 3.84H) 3.49 (d,J=15.26 Hz, 0.64H) 3.54 (s, 1.92H) 3.83 (s, 1.08H) 3.91 (s, 3H) 4.08 (d,J=15.26 Hz, 0.36H) 5.29 (d, J=15.26 Hz, 0.36H) 5.50 (d, J=14.95 Hz,0.64H) 6.98-7.06 (m, 1H) 7.16 (d, J=2.44 Hz, 0.36H) 7.23 (d, J=2.44 Hz,0.64H) 7.30 (d, J=8.55 Hz, 0.64H) 7.34 (d, J=8.55 Hz, 0.36H) 7.56 (dd,J=8.55, 1.53 Hz, 0.64H) 7.63 (dd, J=8.55, 1.53 Hz, 0.36H) 7.88 (d,J=8.55 Hz, 0.64H) 7.91 (d, J=8.55 Hz, 0.36H) 8.12 (s, 0.36H) 8.33 (d,J=1.53 Hz, 0.64H).

An alternative procedure for the preparation of the title compounds isprovided below.

To a flame dried, four necked, 1 L round bottom flask equipped with amechanical stirrer, N2 inlet and a thermometer, under N2, was chargedsodium hydride (95%) (3.09 g, 129.2 mmol) and dry DMF (200 mL). Withvigorous stirring, trimethylsulfoxonium iodide (32.5 g, 147.3 mmol)portion wise during which time the temperature rose to 30° C. Afterstirring for 30 mins, a solution of7H-Indolo[2,1-a][2]benzazepine-6-carboxylic acid,13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-(methoxy)-,methyl ester (33.8 g, 61.3 mmol) in dry DMF (70 mL) was added quickly.The reaction mixture was stirred below 30° C. for 30 mins and thenpoured into an ice cold solution of 1 N HCl (130 mL) in H2O (2 L)portion wise. After the resulting suspension was mechanically stirredfor 1 h, the precipitates were filtered and the filter cake was washedwith H2O (100 mL). The filter cake was partitioned between EtOAc and 0.5N HCl (1:1, 4 L). The organic phase was separated, washed with H2O (1 L)and brine (1 L), dried over MgSO₄, filtered and concentrated in vacuo.The residue was dissolved in EtOAc (150 mL), and the solution wasfiltered through a silica gel pad (300 g in hexane) and rinsed with 50%EtOAc in hexane (5 L). The filtrate was concentrated in vacuo to give aslightly yellow solid which was triturated with 10% EtOAc in TBME (220mL) from 50° C. to 0° C. to givecycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,methyl ester, (+/−)- as a white solid (26.1 g, 75% yield). HPLC purity,100%. ¹H NMR (DMSO-d₆, 300 MHz) δ 11.61 (s, 1H), 8.47 (s, 0.5H), 8.25(s, 0.5H), 7.81-7.88 (m, 1H), 7.57-7.63 (m, 1H), 7.23-7.29 (m, 2H),7.01-7.07 (m, 1H), 5.43 (d, J=15.0 Hz, 0.5H), 5.22 (d, J=15 Hz, 0.5H),4.04 (dd, J=15.4 and 6.6 Hz, 0.5H), 3.83 (s, 3H), 3.75 (s, 1H),3.08-3.47 (m, 0.5H), 3.29 (s, 3H), 2.73-2.92 (m, 8H), 1.11-1.99 (m,10.5H), 0.20 (m, 0.5H); m/z 566 (M+H)⁺.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,methyl ester, (−)-. A sample of (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-methylester was dissolved in EtOH/CH₃CN 1/1+0.5% DEA at a concentration of 50mg/ml. [The addition of DEA ensures the compound remains in solutionduring the injection process]. This solution was then injected onto aThar SFC-350 preparative SFC under the conditions shown below.

Preparative conditions on Thar SFC-350: Column: Chiralcel OJ-H 5×25 cm;mobile phase: 25% MeOH/CH3CN (1/1) in CO2; pressure (bar): 100; flowrate (ml/min): 240; solution concentration (mg/ml): 50; injection amount(ml): 4.5-5; Cycle time (min/inj): 6.5-7; Temperature (° C.): 45;throughput (g/hr): ˜2; Detector wavelength (nm): 254.

From 371.4 g of racemic starting material, a total of 177.3 g of thedesired second eluting (−) isomer was obtained, containing ˜1 Meq ofdiethylamine. This material was purified using the following procedure.The mixture (24.7 g) dissolved in dichloromethane (800 mL)) was washedsequentially with; 0.5 N HCl (1×400 mL, 1×240 mL), H₂O (2×240 mL), andbrine (2×240 mL). The organic layer was then dried (Anhy. Na₂SO₄),filtered and evaporated to give 22.33 g of(cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,methyl ester, (−)- as a yellow solid (92% recovery). HPLC¹>99% (Rt 2.38min); LC/MS (ES⁺) 566.51 (M+H, 100); [α]_(D) ^(25C)-194.64° (c 1.03,MeOH). Anal. Calcd for C₃₀H₃₅N₃O₆S.0.33H₂O: C, 63.04; H, 6.29; N, 7.35;S, 5.61; H₂O, 1.04. Found: C, 63.07; H, 6.01; N, 7.24; S, 5.58; H₂O,1.03. The NMR shows the absence of Et₂NH. The EE of this material wasdetermined to be >99% using the following analytical HPLC procedure.

Analytical conditions of ee determination on Thar analytical SFC.Analytical Column: Chiralcel OJ (0.46×25 cm, 10 μl); BPR pressure: 100bars; Temperature: 35° C.; Flow rate: 3.0 ml/min; Mobile Phase: 15%MeOH/CH₃CN (1/1) in CO₂; Detector Wavelength: 254 nm; Retention time(min): 4, 6.5.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,(−)-. To a solution of (−)cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-112b-dihydro-11-methoxy-,methyl ester (22.33 g, 39.5 mmol) in MeOH (300 mL) was added 1 N NaOH(120 mL) slowly over 20 min., while maintaining the reaction temperature<30° C. The mixture was stirred at rt under N₂ for 18 h. The HPLCindicated the reaction was complete. To the reaction solution was added1 N HCl (130 mL). After addition was complete, the pH of the reactionmixture was about 2. The methanol in the reaction mixture wasevaporated. Water (300 mL) was added to the mixture which was thenextracted with CH₂Cl₂ (1×600 mL, 1×200 mL). The combined extracts werewashed with H₂O (2×300 mL), brine (2×300 mL), dried (Na₂SO₄) andevaporated to give 20.82 g (96% yield) of the title compound as a yellowsolid. HPLC conditions column: Phenomenoex Synergi Polar-RP 4 um 4.6×50mm; UV: 220 nm; gradient time: 4 min; flow rate: 4 mL/min, 75-100% B;solvent A: 10% MeOH/90% H₂O with 0.2% H₃PO₄, solvent B: 90% MeOH/10% H₂Owith 0.2% H₃PO₄. HPLC>99% (Rt 1.80 min.) LC/MS (ES⁺) 552.25 (M+H, 100);[α]_(D) ^(25C)-166.99°(c 1.00, MeOH). GC analysis: CH₂Cl₂ 4.94%; Anal.Calcd for C₂₉H₃₃N₃O₆S.0.16 H₂O..0.35 CH₂Cl₂: C, 60.37; H, 5.87; N, 7.20;S, 5.49; H₂O, 0.49; CH₂Cl₂, 5.02. Found: C, 59.95; H, 5.89; N, 7.03; S,5.38; H₂O, 0.47; CH₂Cl₂, 4.94.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,(+/−)-. To a solution of (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,methyl ester (100 mg, 0.177 mmol) in THF/Methanol mixture (2.0 mL/2.0mL), 2N NaOH solution (1.0 mL) was added. The reaction mixture washeated at 90° C. under microwave conditions for 5 min. It was thenconcentrated, acidified with 1N HCl solution and extracted with ethylacetate (2×20 mL). The organic layers were combined, dried (MgSO₄),filtered and concentrated. The residue was purified by preparative HPLCto afford the desired product as a light yellow solid, (59 mg, 60%yield). MS m/z 552 (MH⁺), Retention time: 3.850 min. ¹H NMR (300 MHz,MeOD) δ ppm 0.25 (m, 0.38H) 1.14-2.22 (m, 11.62H) 2.69-2.98 (m, 2H) 3.02(s, 2.28H) 3.02 (s, 3.72H) 3.41 (d, J=15.00 Hz, 0.62H) 3.88 (s, 3H) 4.01(d, J=15.00 Hz, 0.38H) 5.26 (d, J=15.00 Hz, 0.38H) 5.45 (d, J=14.64 Hz,0.62H) 6.94-7.02 (m, 1H) 7.13 (d, J=2.56 Hz, 0.38H) 7.21 (d, J=2.20 Hz,0.62H) 7.26 (d, J=8.42 Hz, 0.62H) 7.30 (d, J=8.78 Hz, 0.38H) 7.53 (dd,J=8.42, 1.46 Hz, 0.62H) 7.61 (dd, J=8.60, 1.65 Hz, 0.38H) 7.85 (d,J=8.42 Hz, 0.62H) 7.89 (d, J=8.42 Hz, 0.38H) 8.10 (s, 0.38H) 8.28 (d,J=1.46 Hz, 0.62H).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a, 5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N^(1a)-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aR)-[partial]-. TBTU (437 mg, 1.36 mmol) and DIPEA (0.95 mL, 5.436mmol) were added to a solution of (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-(500 mg, 0.906 mmol) in DMSO (20.0 mL). The reaction mixture was stirredat rt for 15 min.(2S,3R)-3-Amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (280 mg, 1.36mmol) was then added and the reaction mixture was stirred at rtovernight. The reaction mixture was quenched with water and acidifiedwith 1N HCl solution. A brown solid separated which was collected byfiltration. This material was then fractionated by Preparative HPLCunder the following conditions. Column: Waters Sunfire 19 mm×100 mm;Solvent A: 10% CH3CN-90% H2O-0.1% TFA; Solvent B: 90% CH3CN-10% H2O-0.1%TFA; Program: Start with 65% solvent B, initial hold time for 5 min,then gradually increase to 90% solvent B in 30 min with flow rate 25mL/min. Load: 50-60 mg/run.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N^(1a)-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aR)-[partial]- elutes beforeCycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N^(1a)-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aS)-[partial]- under the HPLC conditions described above. Productobtained as a light yellow solid, 230 mg, 36% yield). MS m/703 (MH⁺),Retention time: 3.936 min. ¹H NMR (500 MHz, MeOD) δ ppm 0.14-0.24 (m,2.64H) 0.51 (s, 2.46H) 0.72-2.21 (m, 20.9H) 2.49 (m, 0.18H) 2.62 (m,0.82H) 2.85 (m, 0.18H) 2.96 (m, 0.82H) 3.03 (s, 6H) 3.39 (m, 0.82H)3.49-3.58 (m, 1.64H) 3.71-3.80 (m, 0.36H) 3.90 (s, 3H) 4.17 (d, J=14.65Hz, 0.18H) 5.06 (d, J=14.65 Hz, 0.18H) 5.37 (d, J=14.95 Hz, 0.82H) 6.73(d, J=5.49 Hz, 0.82H) 6.98-7.05 (m, 1H) 7.08 (d, J=4.58 Hz, 0.18H) 7.10(d, J=2.44 Hz, 0.18H) 7.21 (d, J=2.44 Hz, 0.82H) 7.31 (d, J=8.55 Hz,0.82H) 7.34 (d, J=8.55 Hz, 0.18H) 7.59-7.64 (m, 1H) 7.87-7.93 (m, 1H)7.99 (s, 0.18H) 8.09 (d, J=1.22 Hz, 0.82H).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a, 5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N^(1a)-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aS)-[partial]-. TBTU (437 mg, 1.36 mmol) and DIPEA (0.95 mL, 5.436mmol) were added to a solution of (+/−)cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-(500 mg, 0.906 mmol) in DMSO (20.0 mL). The reaction mixture was stirredat rt for 15 min. Then(2S,3R)-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (280 mg, 1.36mmol) was added, and the reaction mixture was stirred at rt overnight.The reaction mixture was quenched with water and then acidified with 1NHCl solution. A brown colored solid separated that was collected byfiltration. This material was then fractionated by preparative HPLCunder the following conditions. Column: Waters Sunfire 19 mm×100 mm;Solvent A: 10% CH3CN-90% H2O-0.1% TFA; Solvent B: 90% CH3CN-10% H2O-0.1%TFA; Program: Start with 65% solvent B, initial hold time for 5 min,then gradually increase to 90% solvent B in 30 min with flow rate 25mL/min. Load: 50-60 mg/run.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N^(1a)-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aS)-[partial]- elutes aftercycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N^(1a)-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aR)-[partial]- under the HPLC conditions described above. Productobtained as a light yellow solid, 215 mg, 34% yield). MS m/703 (MH⁺),Retention time: 4.038 min. ¹H NMR (500 MHz, MeOD) δ ppm 0.20 (m, 0.38H)0.75 (s, 1.86H) 0.76 (s, 1.86H) 0.84 (s, 1.86H) 0.85 (s, 1.14H)0.89-2.18 (m, 18.9H) 2.52 (m, 0.38H) 2.70 (m, 0.62H) 2.85 (m, 0.38H)2.97 (m, 0.62H) 3.03 (s, 2.28H) 3.04 (s, 3.72H) 3.33-3.39 (m, 0.62H)3.43-3.51 (m, 1.24H) 3.73-3.77 (m, 0.38H) 3.78-3.84 (m, 0.38H) 3.90 (s,1.86H) 3.90 (s, 1.14H) 4.14 (d, J=14.65 Hz, 0.38H) 5.11 (d, J=14.65 Hz,0.38H) 5.44 (d, J=15.26 Hz, 0.62H) 6.68 (d, J=4.88 Hz, 0.62H) 6.96-7.03(m, 1H) 7.07 (d, J=5.19 Hz, 0.38H) 7.12 (d, J=2.44 Hz, 0.38H) 7.23 (d,J=2.14 Hz, 0.62H) 7.27 (d, J=8.54 Hz, 0.62H) 7.33 (d, J=8.54 Hz, 0.38H)7.55 (dd, J=8.39, 1.68 Hz, 0.62H) 7.62 (dd, J=8.55, 1.53 Hz, 0.38H) 7.87(d, J=8.54 Hz, 0.62H) 7.91 (d, J=8.55 Hz, 0.38H) 8.08 (d, J=1.22 Hz,0.38H) 8.10 (d, J=1.22 Hz, 0.62H).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,(−)-. 10 N NaOH (2.0 mL, 20 mmol) solution and 4 mL of water were addedto a solution ofcycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N^(1a)-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aR)-[partial]-(160 mg, 0.228 mmol) in THF/MeOH (7 mL/7 mL). Thereaction mixture was heated at 120° C. under microwave conditions for 1hr. It was then concentrated, acidified with conc. HCl solution andextracted with ethyl acetate twice (2×30 mL). The organic layers werecombined, dried (MgSO₄), filtered and concentrated in vacuo to an orangeoil. The crude product was then purified by Prep. HPLC column to affordthe product a light yellow solid, (80 mg, 64% yield). Average specificrotation −130.85°; Solvent MeOH; Wavelength 589 nm; 50 cm cell. MS m/552(MH⁺), Retention time: 3.760 min. ¹H NMR (500 MHz, MeOD) δ ppm 0.27 (m,0.38H) 1.14-2.22 (m, 11.62H) 2.76 (m, 0.38H) 2.80-2.92 (m, 1H) 2.92-3.09(m, 6.62H) 3.45 (d, J=14.95 Hz, 0.62H) 3.90 (s, 1.86H) 3.91 (s, 1.14H)4.04 (d, J=15.26 Hz, 0.38H) 5.28 (d, J=15.26 Hz, 0.38H) 5.47 (d, J=15.26Hz, 0.62H) 6.95-7.05 (m, 1H) 7.15 (d, J=2.75 Hz, 0.38H) 7.23 (d, J=1.83Hz, 0.62H) 7.28 (d, J=8.55 Hz, 0.62H) 7.33 (d, J=8.54 Hz, 0.38H) 7.54(dd, J=8.39, 1.68 Hz, 0.62H) 7.63 (dd, J=8.55, 1.53 Hz, 0.38H) 7.86 (d,J=8.55 Hz, 0.62H) 7.91 (d, J=8.55 Hz, 0.38H) 8.11 (d, J=1.22 Hz, 0.62H)8.29 (d, J=1.22 Hz, 0.38H).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,(+)-. 10 N NaOH (1.8 mL, 18 mmol) solution and 4 mL of water were addedto a solution ofcycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxamide,8-cyclohexyl-N⁵-[(dimethylamino)sulfonyl]-1,12b-dihydro-N^(1a)-[(2R,3S)-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-11-methoxy-,(1aS)-[partial]-(130 mg, 0.185 mmol) in bTHF/MeOH (7 mL/7 mL). Thereaction mixture was heated at 120° C. under microwave conditions for 1hr. It was concentrated, acidified with conc. HCl solution and extractedwith ethyl acetate twice (2×30 mL). The organic layers were combined,dried (MgSO₄), filtered and concentrated in vacuo to give an orange oil.The crude product was then purified by Prep. HPLC column to afford theproduct as a light yellow solid, (68 mg, 67% yield). Average specificrotation +174.73°; Solvent MeOH; Wavelength 589 nm; 50 cm cell MS m/552(MH⁺), Retention time: 3.773 min. ¹H NMR (500 MHz, MeOD) δ ppm 0.27 (m,0.38H) 1.14-2.22 (m, 11.62H) 2.76 (m, 0.38H) 2.80-2.92 (m, 1H) 2.92-3.09(m, 6.62H) 3.45 (d, J=14.95 Hz, 0.62H) 3.90 (s, 1.86H) 3.91 (s, 1.14H)4.04 (d, J=15.26 Hz, 0.38H) 5.28 (d, J=15.26 Hz, 0.38H) 5.47 (d, J=15.26Hz, 0.62H) 6.95-7.05 (m, 1H) 7.15 (d, J=2.75 Hz, 0.38H) 7.23 (d, J=1.83Hz, 0.62H) 7.28 (d, J=8.55 Hz, 0.62H) 7.33 (d, J=8.54 Hz, 0.38H) 7.54(dd, J=8.39, 1.68 Hz, 0.62H) 7.63 (dd, J=8.55, 1.53 Hz, 0.38H) 7.86 (d,J=8.55 Hz, 0.62H) 7.91 (d, J=8.55 Hz, 0.38H) 8.11 (d, J=1.22 Hz, 0.62H)8.29 (d, J=1.22 Hz, 0.38H).

1H-Indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, 1,1-dimethylethylester. To a mechanically stirred solution of2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (80 g, 0.24 m) in drymethylene dichloride(1.2 L) and THF (100 mL) were added activatedmolecular sieves (4 A, 80 g) and silver carbonate (275 g, 0.99 m). Thereaction mixture was cooled to 0° C. and t-Butyl bromide (142 g, 1.04 m)was added drop wise. The mixture was stirred overnight at rt andmonitored by TLC (Hexane-Ethyl acetate 80:20, R_(f)(Product)=0.7). Ifany bromo acid was left unconverted a further 10% of silver carbonatewas added and stirring was continued for an addition 2-4 h. Oncompletion, the reaction mixture was filtered through a thin bed ofcelite. The filtrand was washed with methylene dichloride (500 mL). Thecombined filtrates were concentrated in-vacuo, and the crude productthus obtained was purified by silica gel chromatography: (230-400 mesh,eluted with a gradient of ethyl acetate in pet ether 0-2%). Homogeneousfractions were combined and evaporated under reduced pressure to give 80g (85%) of the title compound. HPLC: 90.1% (RT=6.56 min), Column: C18BDS, (50×4.6 mm), Mobile Phase Gradient of 0.1% TFA in water: ACN(30→100→30), Flow rate 0.8 mL/min. LCMS: 99.8% (RT=4.44 min), Column:Geneis, C1850X4.6 mm Mobile Phase: Gradient of 0.1% Formic acid inwater: ACN (70→95→70), Flow rate: 0.8 mL/min; M−1=376.5; ¹H NMR CDCl₃)(400 MHz) δ 1.37-1.40 (m, 3H, cyc.Hexyl), 1.62 (s, 9H, t-Bu), 1.80-1.94(two sets of m, 3H, & 4H respectively, cyc.Hexyl part), 2.81 (m, 1H, CHof cyc.Hexyl-benzylic), 7.70-7.75 (m, 2H, Indole-H_(4&5)), 8.04 (s, 1H,Indole-H₇), 8.52 (s, 1H, Indole-NH).

1H-Indole-6-carboxylic acid, 3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-,1,1-dimethylethyl ester. tert-Butyl2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (72 g, 0.19 m) wasdissolved in a 1:1 mixture of toluene and ethanol (720 mL) anddegasified. LiCl (23.9 g, 0.51 m) was then added, followed by sodiumcarbonate (720 mL, 1.0 M solution degasified separately,) andPd-tetrakis (13.1 g, 0.011 m). After stirring for 0.25 h,2-formyl-4-methoxyphenylboronic acid (41.1 g, 0.22 m) was added and thereaction mixture was heated to 85° C. for 4 h. The reaction was thenmonitored by TLC, (Hexane-Ethyl acetate 80:20, R_(f) (Product)=0.55). Oncompletion, the reaction mixture was cooled to rt and water (1.0 L) wasadded followed by ethyl acetate (1.0 L). The organic layer was washedwith brine, and dried and concentrated under vacuum to afford the titlecompound as a yellow solid. Yield 75 g (74%). HPLC: 99.7% (RT=6.30 min),Column: C18 BDS (4.6×50 mm), SC-307, Mobile Phase: Gradient of 0.1% TFAin water: ACN (30→100→30), Flow rate 0.8 mL/min. LCMS: 98.0% (RT=5.28min), Column: Geneis, C18 (50×4.6 mm), Mobile Phase: Gradient of 0.1%Formic acid in water: ACN (70→95→70), Flow rate: 0.8 mL/min; M−1=432.2;¹H NMR (DMSO-d₆) (400 MHz) δ 1.40-1.48 (m, 3H, cyc.Hexyl), 1.57 (s, 9H,t-Bu), 1.84-1.90 (m, 7H, cyc.Hexyl part), 3.09 (m, 1H, CH ofcyc.Hexyl-benzylic), 3.84 (s, 3H, OCH₃), 6.55 (d, J=4 Hz, 1H, arylH_(2′)), 7.06 (d, 1H, aryl H_(3′)), 7.08 (s, 1H, aryl H_(6′)), 7.23 (d,1H, Indole-H₅), 7.53 (d, J=8 Hz, 1H, Indole-H₄), 7.70-7.75 (m, 2H,NH+Indole-H₇), 8.06 (s, 1H, CHO).

7H-Indolo[2,1-a][2]benzazepine-6,10-dicarboxylic acid, 13-cyclohexyl-,10-(1,1-dimethylethyl) 6-methyl ester. tert-Butyl3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxylate (62.5g, 0.144 m) was dissolved in dry DMF (1.2 L) and stirred mechanically.Cesium carbonate (84 g, 0.17 m) and methyl2-(dimethoxyphosphoryl)acrylate (65-70% GC pure, 56.2 g, 0.18 m) werethen added and the reaction mixture was heated to 65° C. for 4 h, andthe reaction was monitored by TLC (Hexane-Ethyl acetate 80:20,R_(f)(Product)=0.7). On completion, the mixture was cooled to rt, thenquenched with water (1.0 L). A yellow solid precipitated, which wascollected by filtration and air dried. This material was then slurriedin methanol, filtered, and dried under vacuum to give the product as ayellow powder, (70 g, 90%). HPLC: 99.1% (RT=6.45 min), Column: C18 BDS(4.6×50 mm), Mobile Phase: Gradient of 0.1% TFA in water: ACN(30→100→30), Flow rate 0.8 mL/min. LCMS: 100% (RT=7.00 min), Column:Geneis, C18 (50×4.6 mm), Mobile Phase: Gradient of 0.1% Formic acid inwater: ACN (70→95→70), Flow rate: 0.8 mL/min; M+1=502.2; ¹H NMR (CDCl₃)(400 MHz) δ 1.10-1.30 (m, 3H, cyc.Hexyl), 1.64 (s, 9H, t-Bu), 1.77-2.07(m, 7H, cyc.Hexyl part), 2.80 (m, 1H, CH of cyc.Hexyl-benzylic), 3.84(s, 3H, OCH₃), 3.93 (s, 3H, COOCH₃), 4.15 & 5.65 (two br. peak., 1Heach, allylic CH₂), 6.95 (s, 1H, aryl H_(6′)), 7.01 (d, 1H, arylH_(2′)), 7.53 (d, J=8 Hz, 1H, aryl H_(3′)), 7.70 (d, J=4 Hz, 1H,Indole-H₅), 7.84 (s+d, 2H, olefinic H+Indole-H₄), 8.24 (s, 1H,indole-H₇); ¹³C NMR (CDCl₃) (100.0 MHz) δ 166.92, 165.71, 158.96,142.28, 136.47, 13.50, 134.61, 132.43, 132.01, 129.73, 124.78, 124.68,120.33, 119.39, 119.04, 115.62, 115.05, 111.27, 80.27, 55.49, 52.50,39.09, 36.81, 33.40, 28.38, 27.15, 26.28.

2-Propenoic acid, 2-(dimethoxyphosphinyl)-, methyl ester. To a 5 L fournecked round bottom flask equipped with a mechanical stirrer, acondenser, a temperature controller and a N2 inlet, was chargedparaformaldehyde (40.5 g, 1.35 mol), MeOH (2 L) and piperidine (2 mL).The reaction mixture was heated to reflux under N2 for 3 h. Aftercooling to 50° C., 2-(dimethoxyphosphoryl)acetate (150 g, 0.824 mol) wasadded in one portion. The reaction mixture was continued to reflux for18 h. After cooling to rt, the reaction solution was concentrated invacuo to give a clear colorless oil. The above oil was dissolved in drytoluene (1 L) in a 3 L four necked round bottom flask equipped atemperature controller, a N₂ inlet, a magnetic stirrer and a Dean-Starkapparatus. To the solution was added TsOH.H₂O (5.2 g). The reactionmixture was then refluxed azeotropically to remove methanol for 18 h.After cooling to rt, the solution was concentrated in vacuo to give ayellow oil which was vacuum distilled at 150-155° C./0.2 mmHg to affordthe product as a colorless oil (135.0 g). Purity, 90% based on ¹H NMR.¹H NMR (CDCl₃, 300 MHz) δ 7.0 (dd, J=42.4 and 1.5 Hz, 1H), 6.73 (dd,J=20.5 and 1.8 Hz, 1H), 3.80 (s, 6H), 3.76 (s, 3H).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a, 5(2H)-dicarboxylic acid,8-cyclohexyl-1,12b-dihydro-11-methoxy-, 5-(1,1-dimethylethyl) 1a-methylester, (+/−) Sodium hydride (96 mg, 4 mmol) was added to a stirredsuspension of trimethylsulfoxonium chloride (567 mg, 4.4 mmol) inanhydrous DMSO (10 mL) under nitrogen. The resultant mixture was stirredat rt for 30-45 min and then neat7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylic acid,13-cyclohexyl-3-methoxy-, 10-(1,1-dimethylethyl) 6-methyl ester (1.0, 2mmol) was added in small portions. The suspension was diluted with DMSO(5 mL) and heated at 50° C. for 3-4 h. The reaction mixture was allowedto cool to rt and water was added. A solid separated, which wascollected by filtration and washed with water and then air driedovernight to afford 1.15 g of crude product. This material was purifiedby flash column chromatography (silica gel, 3% MeOH in DCM) to providepure title compound (0.96 g): LC/MS: Retention time 3.816 min; m/e 516(MH⁺). ¹H NMR (400 MHz, CDCl₃): The product was observed to exist asinter-converting rotamers, as evidenced from the compound's NMRspectrum.

The following procedure is an example of a method to effect theresolution of racemiccycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxylic acid,8-cyclohexyl-1,12b-dihydro-11-methoxy-, 5-(1,1-dimethylethyl) 1a-methylester, (+/−). A sample ofcycloprop[d]indolo[2,1-a][2]benzazepine-1a,5(2H)-dicarboxylic acid,8-cyclohexyl-1,12b-dihydro-11-methoxy-, 5-(1,1-dimethylethyl) 1a-methylester, (+/−)− was dissolved in a mixture of isopropanol and acetonitrile(8:2) to give a final concentration of 20 mg/mL. This mixture wasinjected on a preparative chiral SFC chromatography system using thefollowing conditions: Chiralcel OJ-H column, 4.6×250 mm, 5 μm; MobilePhase: 8% MeOH in CO₂; Temp: 35° C.; Flow rate: 2 mL/min for 16 min; UVmonitored (260 nm; Injection: 5 μL of 20.0 mg/mL in IPA:ACN (8:2).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a, 5(2H)-dicarboxylic acid,8-cyclohexyl-1,12b-dihydro-11-methoxy-, 1a-methyl ester, (+/−)-. TFA (5mL) was added to a solution of (+/−)8-Cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(methoxycarbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid, tert-butyl ester (515 mg, 1 mmol) in anhydrous DCM (10 mL). Theresultant solution was stirred at rt for approximately 8 to 12 hr. Thereaction was then evaporated to dryness to afford the title compound(0.47 g, 100%). LC/MS: Retention time 2.245 min; m/e 460 (MH⁺). ¹H NMR(400 MHz, CDCl₃): From the compounds NMR spectrum, the product wasobserved to exist as a mixture of interconverting rotamers.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-1,12b-dihydro-11-methoxy-5-[[[(methylamino)sulfonyl]amino]carbonyl]-,methyl ester. A solution of8-Cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(methoxycarbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid (140 mg, 0.31 mmol) and CDI (64 mg, 0.40 mmol) in THF (3 mL) wasstirred for 1 hr at 60° C. N-methylsulfamide (68 mg, 0.62 mmol) and DBU(71.6 mg, 0.47 mmol) were added and the mixture was stirred at 60° C.overnight. The reaction was then poured into cold water, acidified withdilute hydrochloric acid and extracted into ethyl acetate. The extractswere washed sequentially with dilute hydrochloric acid (0.1 N), andbrine, and then dried (anhy. sodium sulfate), filtered and evaporated toprovide the title compound as a brown solid. ESI-MS m/e 552 (MH⁺). Thismaterial was used without further purification.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-1,12b-dihydro-11-methoxy-5-[[[(methylamino)sulfonyl]amino]carbonyl]-.Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(methylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-,methyl ester was dissolved in THF, MeOH mixture (2 mL, 2 mL). 2.5 M NaOH(aq.) (1.2 mL, 3 mmol) was then added and the reaction was shaken at 22°C. for 2 hr. The solution was then neutralized with 1M HCl (aq.) (3 mL)and concentrated to remove the organic solvents. The residue wasslurried with H₂O and the solids were collected by filtration, washedwith H₂O and dried to yield compound the title compound (160 mg, 0.30mmol). ESI-MS m/e 538 (MH⁺). This material was used without furtherpurification.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(benzylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-(methoxy)-12-(methoxy)-,methyl ester, (+/−)-. A solution of (+/−)8-cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(methoxycarbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid (200 mg, 0.44 mmol) and CDI (92 mg, 0.57 mmol) in THF (5 mL) wasstirred for 1 hr at 60° C. N-benzylsulfamide (164 mg, 0.88 mmol) and DBU(100 mg, 0.66 mmol) were then added and the resultant mixture wasstirred at 60° C. overnight. The reaction was then poured into coldwater, acidified with dilute hydrochloric acid and extracted into ethylacetate. The organic phase was washed hydrochloric acid (0.1 N), brineand dried (sodium sulfate) and evaporated in vacuo to provide the titlecompound as a brown solid. ESI-MS m/e 628 (MH⁺).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-1,12b-dihydro-11-methoxy-5-[[[[(phenylmethyl)amino]sulfonyl]amino]carbonyl]-,(+/−)-. The title compound was prepared using a similar procedure tothat described forcycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[[(methylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy-cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid starting from (+/−)8-cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(methoxycarbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid. ESI-MS m/e 613 (MH+), ¹H NMR (500 MHz, MeOD) δ ppm 1.22-2.20 (m,13H) 3.27-3.31 (m, 1H) 3.47 (d, J=14.95 Hz, 0.6H) 3.92 (d, J=2.44 Hz,3H) 4.04 (d, 0.4H) 4.31 (d, J=2.75 Hz, 2H) 5.24 (d, 0.4H) 5.48 (d, 0.6H)7.02 (d, 1H) 7.17 (d, J=2.75 Hz, 1H) 7.19-7.35 (m, 5H) 7.39 (t, J=7.48Hz, 2H) 7.45-7.52 (m, 1H) 7.80 (d, J=1.53 Hz, 0.4H) 7.85 (dd, J=8.39,6.87 Hz, 1H) 8.22 (d, J=1.53 Hz, 0.6H).

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[(cyclopropylsulfonyl)amino]carbonyl]-1,12b-dihydro-11-methoxy-,(+/−)-. A mixture of (+/−)8-cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(methoxycarbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid (1 equiv), and carbonyldiimidazole (1.5 equiv) in anhydrous THF washeated at 50° C. for 30 min and allowed to cool to rt. Then 1 equiv ofcyclopropanesulfonamide and 1,8-diazabicyclo[5.4.0]undec-7-ene (2 equiv)were added consecutively. The resultant mixture was stirred at rtovernight. After acidic aqueous workup, the isolated crude product waspurified by prep. HPLC. The intermediate ester was then hydrolyzed using1N NaOH in THF-MeOH to afford the title compound. LC/MS: Retention time:2.030 min; m/e 549 (MH⁺). ¹H NMR (400 MHz, CDCl₃): The product wasobserved to exist as inter-converting rotamers, as evidenced from thecompound's NMR spectrum.

Intermediates 27-38 use the experimental procedures that follow untilotherwise noted. LCMS data: Stop time: Gradient time+1 minute; Startingconc: 0% B unless otherwise noted; Ending conc: 100% B unless otherwisenoted; Eluent A: 5% CH₃CN/95% H₂O with 10 mM NH₄OAc (for columns A, Dand E); 10% MeOH/90% H₂O with 0.1% TFA (for columns B and C); Eluent B:95% CH₃CN/5% H₂O with 10 mM NH₄OAc (for columns A, D and E); 90%MeOH/10% H₂O with 0.1% TFA (for columns B and C); Column A: Phenomenex10μ 4.6×50 mm C18; Column B: Phenomenex C18 10μ 3.0×50 mm; Column C:Phenomenex 4.6×50 mm C18 10μ; Column D: Phenomenex Lina C185μ 3.0×50 mm;Column E: Phenomenex 5μ 4.6×50 mm C18; Preparative HPLC data: Conditionsfor H₂O/CH₃CN with 10 mM NH₄OAc buffer; Gradient: Linear over 20 min.unless otherwise noted; Starting conc: 15% B unless otherwise noted;Ending conc: 100% B; Eluent A: 5% CH₃CN/95% H₂O with 10 mM NH₄OAc;Eluent B:95% CH₃CN/5% H₂O with 10 mM NH₄OAc; Column: Sunfire Prep C₁₈OBD 5μ 30×100 mm; Conditions for H₂O/MeOH with 0.1% TFA buffer;Gradient: Linear over 20 min. unless otherwise noted; Starting conc: 30%B unless otherwise noted; Ending conc: 100% B; Eluent A: 10% MeOH/90%H₂O with 0.1% TFA; Eluent B: 90% MeOH/10% H₂O with 0.1% TFA; Column:phenomenex 21×100 mmC18H₂O.

Cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid,8-cyclohexyl-5-[[(cyclopropylsulfonyl)amino]carbonyl]-1,12b-dihydro-11-methoxy-,(+/−)-. A mixture of (+/−)8-cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(methoxycarbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid (1 equiv), and carbonyldiimidazole (1.5 equiv) in anhydrous THF washeated at 50° C. for 30 min and allowed to cool to rt. Then 1 equiv ofcyclopropanesulfonamide and 1,8-diazabicyclo[5.4.0]undec-7-ene (2 equiv)were added consecutively. The resultant mixture was stirred at rtovernight. After acidic aqueous workup, the isolated crude product waspurified by prep. HPLC. The intermediate ester was then hydrolyzed using1N NaOH in THF-MeOH to afford the title compound. LC/MS: Retention time:2.030 min; m/e 549 (MH⁺). ¹H NMR (400 MHz, CDCl₃): The product wasobserved to exist as inter-converting rotamers, as evidenced from thecompound's NMR spectrum.

13-Cyclohexyl-3-methoxy-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid. Trifluoroacetic acid (30 mL) was added dropwise to a stirringslurry of 10-tert-butyl 6-methyl13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate(10 g, 20 mmol) in dichloroethane (30 mL) under N₂. The clear dark greensolution was stirred at rt for 2.5 h, concentrated to dryness andstirred with EtOAc (100 mL) overnight. The solids were collected byfiltration, washed with EtOAc and Et₂O to yield13-cyclohexyl-3-methoxy-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid (8.35 g, 18.8 mmol, 94%) was as a yellow solid which was usedwithout further purification. ¹HNMR (300 MHz, CDCl₃) δ 1.13-2.16 (m,10H), 2.74-2.88 (m, 1H), 3.84 (s, 3H), 3.89 (s, 3H), 4.06-4.29 (m, 1H),5.54-5.76 (m, 1H), 6.98 (d, J=2.6 Hz, 1H), 7.08 (dd, J=8.4, 2.6 Hz, 1H),7.52 (d, J=8.4 Hz, 1H), 7.78 (dd, J=8.8, 1.1 Hz, 1H), 7.80 (s, 1H), 7.86(d, J=8.8 Hz, 1H), 8.34 (d, J=1.1 Hz, 1H). LCMS: m/e 446 (M+H)⁺, rettime 3.21 min, column B, 4 minute gradient.

Methyl13-cyclohexyl-10-((cyclopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate.1,1′-Carbonyldiimidazole (1.82 g, 11.2 mmol) was added to a slurry of13-cyclohexyl-3-methoxy-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid (3.85 g, 8.65 mmol) in THF (15 mL). The reaction mixture was heatedat 60° C. for 1.5 h, cooled to rt, treated with cyclopropanesulfonamide(1.36 g, 11.2 mmol), stirred 10 min and then treated with the dropwiseaddition of a solution of DBU (2.0 mL, 13 mmol) in THF (3 mL). Thereaction mixture was stirred at rt overnight, diluted with EtOAc (100mL) and washed with H₂O (˜30 mL), 1N HCl (aq.) (2×50 mL) and brine (˜30mL). The combined aqueous layers were extracted with EtOAc (100 mL) andthe organic layer was washed with 1N HCl (aq.) (˜50 mL). The combinedorganic layers were washed with brine (˜30 mL), dried (MgSO₄), filteredand concentrated. The residue was stirred with Et₂O (˜100 mL) for 2 hand the solids were collected by filtration, rinsed with Et₂O and driedto yield methyl13-cyclohexyl-10-((cyclopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate(4.24 g, 7.73 mmol, 89%) as a pale yellow solid which was used withoutfurther purification. ¹HNMR (300 MHz, CDCl₃) δ 1.08-2.13 (m, 14H),2.73-2.87 (m, 1H), 3.13-3.24 (m, 1H), 3.82 (s, 3H), 3.89 (s, 3H),4.04-4.27 (m, 1H), 5.50-5.71 (m, 1H), 6.98 (d, J=2.6 Hz, 1H), 7.08 (dd,J=8.8, 2.6 Hz, 1H), 7.44 (dd, J=8.4, 1.1 Hz, 1H), 7.50 (d, J=8.8 Hz,1H), 7.80 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 8.11 (br s, 1H), 8.78 (br s,1H). LCMS: m/e 549 (M+H)⁺, ret time 3.79 min, column B, 4 minutegradient.

13-Cyclohexyl-10-((cyclopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylicacid. Methyl13-cyclohexyl-10-((cyclopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate(1.0 g, 1.8 mmol) was dissolved into MeOH//THF (1:1, 24 mL) and treatedwith 1M aqueous NaOH (5 mL). The reaction mixture was stirred and heatedat 60° C. for 1.5 h and cooled to rt. The clear solution was neutralizedwith 1M aqueous HCl (5 mL) and concentrated to remove organic solvents.The resultant solids were collected by filtration, washed with H₂O anddried under vacuum to yield13-cyclohexyl-10-((cyclopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylicacid (1.0 g, 1.7 mmol, 94%) as a bright yellow solid (with 0.75 equiv.of THF) which was used without further purification. ¹HNMR (300 MHz,CD₃OD) δ 1.11-2.24 (m, 17H, 3H from THF), 2.81-2.96 (m, 1H), 3.17-3.28(m, 1H), 3.69-3.79 (m, 3H, from THF), 3.94 (s, 3H), 4.07-4.33 (m, 1H),5.55-5.81 (m, 1H), 7.14-7.24 (m, 2H), 7.55-7.64 (m, 2H), 7.88-7.94 (m,2H), 8.20 (br s, 1H). LCMS: m/e 535 (M+H)⁺, ret time 3.73 min, column B,4 minute gradient.

Methyl8-cyclohexyl-5-((cyclopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylate.To slurry of sodium hydride (60% dispersion in mineral oil, 370 mg, 9.2mmol) in DMSO (8 mL) stirring under N₂ was added trimethylsulfoxoniumiodide (2.03 g, 9.2 mmol). The reaction mixture was stirred for 45 minand then methyl13-cyclohexyl-10-((cyclopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate(2.2 g, 4.0 mmol) in DMSO (5 mL) was added (flask rinsed with DMSO (2×3mL)). The reaction mixture was stirred 1 h, poured into 0.25N HCl (100mL), and extracted with EtOAc (150 mL). The organic layer was washedwith brine (20 mL) and the combined aqueous layers were extracted withEtOAc (100 mL). The combine organic layers were washed with brine (˜20mL), dried (MgSO₄), filtered and concentrated to dryness. The residuewas stirred with EtOAc/Et₂O (1:3, 50 mL) and the solids were removed byfiltration. The motherliquor was concentrated and dried under highvacuum to yield methyl8-cyclohexyl-5-((cyclopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylate(1.92 g, 3.4 mmol, 85%) as a yellow solid which was used without furtherpurification. Presents as a ˜2:1 mixture of rotamers or atrope isomers.¹HNMR (300 MHz, CD₃OD) δ 0.19-0.26 (m, 0.4H), 0.78-2.19 (m, 15.6H),2.64-3.02 (m, 2H), 3.16-3.28 (m, 1H), 3.41 (d, J=15.0 Hz, 0.6H), 3.51(s, 1.8H), 3.80 (s, 1.2H), 3.88 (s, 3H), 4.00 (d, J=15.0 Hz, 0.4H), 5.22(d, J=15.0 Hz, 0.4H), 5.42 (d, J=15.0 Hz, 0.6H), 6.93-7.01 (m, 1H), 7.12(d, J=2.6 Hz, 0.4H), 7.19 (d, J=2.6 Hz, 0.6H), 7.25 (d, J=8.8 Hz, 0.6H),7.29 (d, J=8.8 Hz, 0.4H), 7.55 (dd, J=8.8, 1.5 Hz, 0.6H), 7.63 (dd,J=8.8, 1.5 Hz, 0.4H), 7.85 (d, J=8.8 Hz, 0.6H), 7.88 (d, J=8.8 Hz,0.4H), 8.08 (d, J=1.5 Hz, 0.4H), 8.31 (d, J=1.5 Hz, 0.6H). LCMS: m/e 563(M+H)⁺, ret time 3.75 min, column B, 4 minute gradient.

8-Cyclohexyl-5-((cyclopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid. Methyl8-cyclohexyl-5-((cyclopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylate(1.92 g, 3.41 mmol) was dissolved into MeOH//THF (1:1, 40 mL) andtreated with 1M aqueous NaOH (8 mL). The reaction mixture was stirredand heated at 60° C. for 2 h and cooled to rt. The clear solution wasneutralized with 1M aqueous HCl (8 mL) and concentrated to removeorganic solvents. The resultant solids were collected by filtration,washed with H₂O and dried under vacuum to yield8-cyclohexyl-5-((cyclopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (1.66 g, 3.03 mmol, 89%) as a yellow powder which was used withoutfurther purification. Presents as a 1:1 mixture of rotamers or atropeisomers. ¹HNMR (300 MHz, CDCl₃) δ 0.32 (t, J=6.2 Hz, 0.5H), 0.71-2.12(m, 15.5H), 2.61-2.94 (m, 2H), 3.16-3.27 (m, 1H), 3.41 (d, J=15.0 Hz,0.5H), 3.82 (s, 1.5H), 3.86 (s, 1.5H), 3.99 (d, J=15.0 Hz, 0.5H), 5.28(d, J=15.0 Hz, 0.5H), 5.49 (d, J=15.0 Hz, 0.5H), 6.85 (dd, J=8.4, 2.6Hz, 0.5H), 6.91 (dd, J=8.4, 2.6 Hz, 0.5H), 6.96 (d, J=2.6 Hz, 0.5H),7.08 (d, J=2.6 Hz, 0.5H), 7.19 (d, J=8.4 Hz, 0.5H), 7.24 (d, J=8.4 Hz,0.5H), 7.61 (d, J=8.4 Hz, 0.5H), 7.67 (d, J=8.4 Hz, 0.5H), 7.83 (d,J=8.4 Hz, 0.5H), 7.85 (d, J=8.4 Hz, 0.5H), 8.06 (s, 0.5H), 8.35 (s,0.5H), 9.31-10.35 (m, 1H). LCMS: m/e 547 (M−H)⁻, ret time 2.06 min,column A, 4 minute gradient.

Methyl13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate.1,1′-Carbonyldiimidazole (262 mg, 1.62 mmol) was added to a slurry of13-cyclohexyl-3-methoxy-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid (603 mg, 1.36 mmol) in THF (3 mL). The reaction mixture was heatedat 60° C. for 1.5 h, cooled to rt, treated with propane-2-sulfonamide(200 mg, 1.62 mmol), stirred 10 min and then treated with the dropwiseaddition of a solution of DBU (0.27 mL, 1.8 mmol) in THF (0.75 mL). Thereaction mixture was stirred at rt overnight, diluted with EtOAc (15 mL)and washed with H₂O (˜5 mL), 1N HCl (aq.) (2×10 mL) and brine (˜5 mL).The combined aqueous layers were extracted with EtOAc (15 mL) and theorganic layer was washed with 1N HCl (aq.) (˜10 mL). The combinedorganic layers were washed with brine (˜5 mL), dried (MgSO₄), filteredand concentrated. The residue was stirred with Et₂O (˜15 mL) for 2 h andthe solids were collected by filtration, rinsed with Et₂O and dried toyield methyl13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate(640 mg, 1.2 mmol, 85%) as a bright yellow solid which was used withoutfurther purification. ¹HNMR (300 MHz, CDCl₃) δ 1.12-2.13 (m, 10H), 1.47(d, J=7.0 Hz, 6H), 2.73-2.86 (m, 1H), 3.82 (s, 3H), 3.89 (s, 3H),4.06-4.26 (m, 1H), 4.09 (septet, J=7.0 Hz, 1H), 5.51-5.71 (m, 1H), 6.98(d, J=2.6 Hz, 1H), 7.08 (dd, J=8.4, 2.6 Hz, 1H), 7.44 (dd, J=8.4, 1.5Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.87 (d, J=8.4 Hz, 1H),8.10 (d, J=1.5 Hz, 1H), 8.57 (s, 1H). LCMS: m/e 551 (M+H)⁺, ret time3.87 min, column B, 4 minute gradient.

Methyl8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylate.To slurry of sodium hydride (60% dispersion in mineral oil, 97 mg, 2.4mmol) in DMSO (2 mL) stirring under N₂ was added trimethylsulfoxoniumiodide (530 g, 2.4 mmol). The reaction mixture was stirred for 45 minand then methyl13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate(578 g, 1.05 mmol) in DMSO (1.5 mL) was added (flask rinsed with DMSO(2×0.75 mL)). The reaction mixture was stirred 1 h, poured into 0.25NHCl (25 mL), and extracted with EtOAc (40 mL). The organic layer waswashed with brine (10 ml) and the combined aqueous layers were extractedwith EtOAc (25 mL). The combine organic layers were washed with brine(˜10 mL), dried (MgSO₄), filtered and concentrated to dryness. Theresidue was stirred with EtOAc/Et₂O (1:4, mL) and the solids wereremoved by filtration. The motherliquor was concentrated and dried underhigh vacuum to yield methyl8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylate(620 mg, 1.0 mmol, quant.) as a yellow solid which was used withoutfurther purification. Presents as a ˜2:1 mixture of rotamers or atropeisomers. ¹HNMR (300 MHz, CDCl₃) δ 0.32-0.39 (m, 0.4H), 0.77-2.09 (m,17.6H), 2.60-2.96 (m, 2H), 3.41 (d, J=15.0 Hz, 0.6H), 3.53 (s, 1.8H),3.79 (s, 1.2H), 3.87 (s, 3H), 4.02-4.14 (m, 1.4H), 5.14 (d, J=15.0 Hz,0.4H), 5.39 (d, J=15.0 Hz, 0.6H), 6.89 (dd, J=8.4, 2.6 Hz, 0.4H), 6.91(dd, J=8.4, 2.6 Hz, 0.6H), 7.00 (d, J=2.6 Hz, 0.4H), 7.11 (d, J=2.6 Hz,0.6H), 7.23 (d, J=8.4 Hz, 0.6H), 7.25 (d, J=8.4 Hz, 0.4H), 7.38 (dd,J=8.4, 1.5 Hz, 0.6H), 7.43 (dd, J=8.4, 1.5 Hz, 0.4H), 7.83 (d, J=8.4 Hz,0.6H), 7.86 (d, J=8.4 Hz, 0.4H), 7.96 (d, J=1.5 Hz, 0.4H), 8.20 (d,J=1.5 Hz, 0.6H), 8.39 (s, 0.4H), 8.43 (s, 0.6H). LCMS: m/e 563 (M−H)⁻,ret time 3.00 min, column A, 4 minute gradient.

8-Cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid. Methyl8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylate(606 mg, 1.07 mmol) was dissolved into MeOH//THF (1:1, 14 mL) andtreated with 1M aqueous NaOH (2.5 mL). The reaction mixture was stirredand heated at 60° C. for 2 h and cooled to rt. The clear solution wasneutralized with 1M aqueous HCl (2.5 mL) and concentrated to removeorganic solvents. The residue was stirred with H₂O (10 mL) overnight andthe resultant solids were collected by filtration, washed with H₂O anddried under vacuum to yield8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-1′-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (530 mg, 0.96 mmol, 90%) as a bright yellow solid which was usedwithout further purification. Presents as a ˜2:1 mixture of rotamers oratrope isomers. ¹HNMR (300 MHz, CD₃OD) δ 0.23-0.30 (m, 0.4H), 0.80-2.24(m, 17.6H), 2.70-3.11 (m, 2H), 3.46 (d, J=15.0 Hz, 0.6H), 3.95 (s, 3H),3.93-4.10 (m, 1.4H), 5.29 (d, J=15.0 Hz, 0.4H), 5.48 (d, J=15.0 Hz,0.6H), 6.98-7.05 (m, 1H), 7.16 (d, J=2.6 Hz, 0.4H), 7.23 (d, J=2.6 Hz,0.6H), 7.29 (d, J=8.8 Hz, 0.6H), 7.33 (d, J=8.8 Hz, 0.4H), 7.56 (dd,J=8.8, 1.5 Hz, 0.6H), 7.64 (dd, J=8.4, 1.5 Hz, 0.4H), 7.87 (d, J=8.8 Hz,0.6H), 7.92 (d, J=8.4 Hz, 0.4H), 8.13 (d, J=1.5 Hz, 0.4H), 8.31 (d,J=1.5 Hz, 0.6H). LCMS: m/e 551 (M+H)⁺, ret time 3.74 min, column B, 4minute gradient.

Methyl10-((aminosulfonyl)carbamoyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate.1,1′-Carbonyldiimidazole (1.23 g, 7.60 mmol) was added to a slurry of13-cyclohexyl-3-methoxy-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid (2.6 g, 5.8 mmol) in THF (11 mL). The reaction mixture was heatedat 60° C. for 1.5 h, cooled to rt, treated with sulfamide (1.12 g, 11.7mmol), stirred 10 min and then treated with the dropwise addition of asolution of DBU (1.8 mL, 11.7 mmol) in THF (3 mL). The reaction mixturewas stirred at rt for 3 h, diluted with EtOAc (80 mL) and CH₂Cl₂ (100mL) and concentrated to dryness. The residue was diluted with CH₂Cl₂(100 mL) and washed with 1N HCl (aq.) (2×100 mL). The combined aqueouslayers were extracted with CH₂Cl₂ (100 mL) and the combined organiclayers were washed with ½ saturated brine (˜50 mL), dried (MgSO₄),filtered and concentrated. The residue was stirred with Et₂O (˜75 mL)for 1 h and the solids were collected by filtration, rinsed with Et₂Oand dried to yield methyl10-((aminosulfonyl)carbamoyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate(2.8 g, 5.3 mmol, 91%) as a bright yellow solid which was used withoutfurther purification. ¹HNMR (300 MHz, CDCl₃) δ 1.08-2.10 (m, 10H),2.71-2.84 (m, 1H), 3.79 (s, 3H), 3.89 (s, 3H), 4.00-4.18 (m, 1H),5.50-5.64 (m, 1H), 5.68 (s, 2H), 6.97 (d, J=2.6 Hz, 1H), 7.07 (dd,J=8.8, 2.6 Hz, 1H), 7.46 (dd, J=8.4, 1.5 Hz, 1H), 7.49 (d, J=8.8 Hz,1H), 7.78 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 8.10 (br s, 1H), 9.49 (s,1H). LCMS: m/e 524 (M+H)⁺, ret time 3.60 min, column B, 4 minutegradient.

10-((Aminosulfonyl)carbamoyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylicacid. Methyl10-((aminosulfonyl)carbamoyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate(725 mg, 1.39 mmol) was dissolved into MeOH//THF (1:1, 16 mL) andtreated with 1M aqueous NaOH (3 mL). The reaction mixture was stirredand heated at 60° C. for 0.5 h and cooled to rt. The reaction solutionwas diluted with MeOH/H₂O (2:1, 15 mL), neutralized with 1M aqueous HCl(3 mL) and concentrated to remove organic solvents. The resultant solidswere collected by filtration, washed with H₂O and dried under vacuum toyield10-((aminosulfonyl)carbamoyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylicacid (650 g, 1.3 mmol, 92%) as a bright yellow solid which was usedwithout further purification. ¹HNMR (300 MHz, CDCl₃) δ 1.16-2.22 (m,10H), 2.82-2.96 (m, 1H), 3.94 (s, 3H), 4.07-4.29 (m, 1H), 5.57-5.80 (m,1H), 7.14-7.23 (m, 2H), 7.55-7.63 (m, 2H), 7.88-7.94 (m 2H), 8.18 (s,1H). LCMS: m/e 510 (M+H)⁺, ret time 2.85 min, column B, 4 minutegradient.

Methyl5-((aminosulfonyl)carbamoyl)-8-cyclohexyl-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylate.To slurry of sodium hydride (60% dispersion in mineral oil, 350 mg, 8.8mmol) in DMSO (8 mL) stirring under N₂ was added trimethylsulfoxoniumiodide (1.93 g, 8.8 mmol) in three portions. The reaction mixture wasstirred for 0.5 h and then methyl10-((aminosulfonyl)carbamoyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate(2.0 g, 3.8 mmol) in DMSO (8 mL) was added (flask rinsed with DMSO (2×2mL)). The reaction mixture was stirred 1 h, poured into 0.25N HCl (100mL), and diluted with CH₂Cl₂ (100 mL). The solution was filtered tocollect solids, and the organic layer of the motherliquor was separatedand concentrated to dryness. The residue was dissolved into EtOAc (˜150mL) was washed with H₂O (˜50 mL) and brine (˜50 mL) dried (MgSO₄),filtered and concentrated to dryness. The residue was stirred withEtOAc/Et₂O (4:1, 50 mL) and the solids were collected by filtration andwashed with EtOAc. These solids were combined with the initiallycollected solids to yield methyl5-((aminosulfonyl)carbamoyl)-8-cyclohexyl-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylate(1.39 g, 2.6 mmol, 68%) as a tan solid which was used without furtherpurification. Presents as a 1:1 mixture of rotamers or atrope isomers.¹HNMR (300 MHz, DMSO-d₆) δ 0.13-0.21 (m, 0.5H), 1.06-2.12 (m, 11.5H),2.64-2.94 (m, 2H), 3.46 (s, 1.5H), 3.49 (d, J=15.0 Hz, 0.5H), 3.75 (s,1.5H), 3.85 (s, 3H), 4.02 (d, J=15.0 Hz, 0.5H), 5.21 (d, J=15.0 Hz,0.5H), 5.42 (d, J=15.0 Hz, 0.5H), 6.99-7.09 (m, 1H), 7.17-7.31 (m, 1H),7.41 (s, 0.5H), 7.43 (s, 0.5H), 7.66-7.56 (m, 1H), 7.82 (d, J=8.4 Hz,0.5H), 7.87 (d, J=8.8 Hz, 0.5H), 8.25 (s, 0.5H), 8.47 (s, 0.5H), 11.62(s, 0.5H), 11.69 (s, 0.5H). LCMS: m/e 538 (M+H)⁺, ret time 3.56 min,column B, 4 minute gradient.

5-((Aminosulfonyl)carbamoyl)-8-cyclohexyl-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid. Methyl5-((aminosulfonyl)carbamoyl)-8-cyclohexyl-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylate(1.1 mg, 2.0 mmol) was dissolved into MeOH//THF (1:1, 24 mL) and treatedwith 1M aqueous NaOH (5 mL). The reaction mixture was stirred and heatedat 60° C. for 2 h and cooled to rt. The clear solution was neutralizedwith 1M aqueous HCl (5 mL) and concentrated to remove organic solvents.The residue was stirred with H₂O (10 mL) for 1 h and the resultantsolids were collected by filtration, washed with H₂O and dried undervacuum to yield5-((aminosulfonyl)carbamoyl)-8-cyclohexyl-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (1.05 mg, 2.0 mmol, 98%) as a light yellow solid which was usedwithout further purification. Presents as a 1:1 mixture of rotamers oratrope isomers. ¹HNMR (300 MHz, DMSO-d₆) δ 0.08-0.17 (m, 0.5H),0.79-2.13 (m, 11.5H), 2.65-2.94 (m, 2H), 3.44 (d, J=14.6 Hz, 0.5H), 3.85(s, 3H), 3.96 (d, J=14.6 Hz, 0.5H), 5.20 (d, J=14.6 Hz, 0.5H), 5.40 (d,J=14.6 Hz, 0.5H), 6.98-7.08 (m, 1H), 7.17-7.46 (m, 4H), 7.58 (d, J=8.1Hz, 0.5H), 7.62 (d, J=8.1 Hz, 0.5H), 7.81 (d, J=8.8 Hz, 0.5H), 7.87 (d,J=8.8 Hz, 0.5H), 8.25 (s, 0.5H), 8.44 (s, 0.5H), 11.48-13.19 (m, 2H).LCMS: m/e 524 (M+H)⁺, ret time 3.51 min, column B, 4 minute gradient.

Intermediates 40-44 use the experimental procedures that follow untilnoted.

Dry NaH (96 mg, 4 mmol) was added to a stirred suspension oftrimethylsulfoxonium chloride (567 mg, 4.4 mmol) in an. DMSO (10 mL)under nitrogen. The resultant mixture was stirred at rt for 30-45 minand then neat olefin (1.0, 2 mmol) was added in small portions. Thesuspension was diluted with DMSO (5 mL) and heated at 50° C. for 3-4 h.Reaction mixture was allowed to cool to rt and water was added.Precipitated solid was filtered and washed with water and then air driedovernight to afford 1.15 g of crude product which was purified by flashcolumn chromatography (silica gel, 3% MeOH in DCM), to provide puredesired cyclopropyl compound (0.96 g), as a off-white solid: LC/MS:Retention time 3.816 min; m/e 516 (MH⁺). ¹H NMR (400 MHz, CDCl₃): Theproduct was observed to exist as inter-converting rotamers.

The tert-butyl ester (515 mg, 1 mmol) and TFA (5 mL) in an. DCM (10 mL)was stirred at rt until hydrolysis is complete (8-12 hr). Excess TFA andDCM were evaporated to dryness to afford desired acid (0.47 g, 100%) asa light beige solid.

LC/MS: Retention time 2.245 min; m/e 460 (MH⁺), ¹H NMR (400 MHz, CDCl₃):The product was observed to exist as inter-converting rotamers.

General procedure. A mixture of acid (1 equiv) and carbonyldiimidazole(1.5 equiv) in an. THF was heated at 50° C. for 30 min and allowed tocool to rt. Then 1 equiv of either sulfamide (R═NR₂) or sulfonamide(R=alkyl or aryl) and DBU (2 equiv) were added consecutively. Theresultant mixture was stirred at rt overnight. After acidic aqueousworkup, isolated crude product was purified by prep. HPLC to afford theproduct.

Methyl ester moiety was hydrolyzed using 1N NaOH in THF-MeOH to providethe corresponding acids.

Acid derivatives (1 equiv) were combined with corresponding amine (RRNH,1.2 equiv), triethylamine (2-3 equiv) and TBTU (1.3 equiv) in an. DMFand stirred at rt for 1-2 h until completion of the amide coupling.Isolated crude products were purified by prep. HPLC to provide desiredamides.

Intermediates 45-49 described below were analyzed by the following LC/MSmethod: Analysis Conditions: Column: PHENOMENNEX-LUNA 3.0×50 mm S10;Mobile Phase: (A) 10:90 methanol-water; (B) 90:10 methanol-water;Buffer: 0.1% TFA; Gradient Range: 0-100% B; Gradient Time: 2 min; FlowRate: 4 mL/min; Analysis Time: 3 min; Detection: Detector 1: UV at 220nm; Detector 2: MS (ESI+)/.

(+/−)-8-Cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(methoxycarbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid, tert-butyl ester. LC/MS: Retention time 3.816 min; m/e 516 (MH⁺).¹H NMR (400 MHz, CDCl₃): The product was observed to exist asinter-converting rotamers.

(+/−)-8-Cyclohexyl-1,1a,2,12b-tetrahydro-11-methoxy-1a-(methoxycarbonyl)-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxylicacid. Retention time 2.245 min; m/e 460 (MH⁺), ¹H NMR (400 MHz, CDCl₃).The product was observed to exist as inter-converting rotamers.

(+/−)-8-cyclohexyl-5-(morpholinosulfonylcarbamoyl)-1,1a,2,12b-tetrahydro-11-methoxy-cycloprop[d]indolo[2,1-a][2]benzazepine-1a-carboxylicacid. The product was purified by prep HPLC and isolated as a beigesolid. LC/MS: Retention time: 1.968 min; m/e 460 (MH⁺). ¹H NMR (400 MHz,CDCl₃). The product was observed to exist as inter-converting rotamers.

(+/−)-8-cyclohexyl-5-(4-methylpiperazin-1-ylsulfonylcarbamoyl)-1,1a,2,12b-tetrahydro-11-methoxy-cycloprop[d]indolo[2,1-a][2]benzazepine-1a-carboxylicacid. The product was purified by prep HPLC and isolated in mono TFAsalt form as a beige solid. LC/MS: Retention time: 1.687 min; m/e 607(MH⁺). ¹H NMR (400 MHz, CDCl₃). The product was observed to exist asinter-converting rotamers.

(+/−)-8-cyclohexyl-5-(cyclopropylsulfonylcarbamoyl)-1,1a,2,12b-tetrahydro-11-methoxy-cycloprop[d]indolo[2,1-a][2]benzazepine-1a-carboxylicacid. LC/MS: Retention time: 2.030 min; m/e 549 (MH⁺). ¹H NMR (400 MHz,CDCl₃): The product was observed to exist as inter-converting rotamers.

Intermediates 50-60 were analyzed by the following LC/MS method: Start %B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate:4 ml/min; Wavelenth: 220; Solvent A: 10% MeOH/90% H₂O/0.1%Trifluoroacetic Acid; Solvent B: 10% H₂O/90% MeOH/0.1% TrifluoroaceticAcid; Column: XBridge 4.6×50 mm S5.

A mixture of the acid (1.3 g, 2.83 mmol) and CDI (0.64 g, 3.97 mmol) inTHF (20 mL) was heated at 50° C. for 0.5 h, cooled down and addedmethylsulfonamide (0.4 g, 4.2 mmol) and DBU (0.264 mL, 1.77 mmol). Themixture was stirred for 20 h and diluted with EtOAc, washed with cold 1NHCl (2×), brine, dried (MgSO4), removed the solvent and purified byflash (Biotage 40 M) to afford the compound 1-2 (1.28 g, 85%) as a paleyellow solid. LC-MS retention time: 3.51; MS m/z 537 (M+H). Compound 1-2was observed to exist as inter-converting rotamers. The major isomer: ¹HNMR (400 MHz, CHLOROFORM-D) δ ppm 1.11-2.17 (m, 12H), 2.84-2.98 (m, 2H),3.43 (d, J=14.86 Hz, 1H), 3.49 (s, 3H), 3.55 (s, 3H), 3.89 (s, 3H), 5.40(d, J=15.11 Hz, 1H), 6.91-6.96 (m, 1H), 7.13 (d, J=2.52 Hz, 1H),7.22-7.27 (m, 1H), 7.39 (dd, J=8.31, 1.51 Hz, 1H), 7.85 (d, J=8.81 Hz,1H), 8.23 (d, J=1.26 Hz, 1H), 8.75 (s, 1H).

To a solution of the ester (1.28 g, 2.4 mmol) in THF (5 mL) and MeOH (5mL) was added NaOH (1N, 12 mL, 12 mmol). After being stirred at roomtemperature for 3 h, the mixture was diluted with EtOAc, washed withcold 1N HCl, brine, dried (MgSO4), and removed the solvent in vacuo toafford the acid as a beige solid (1.20 g, 96%). LC-MS retention time:3.46; MS m/z 523 (M+H). The acid was observed to exist asinter-converting rotamers (˜1/1) ¹H NMR (400 MHz, CHLOROFORM-D).

Typical general procedure for amine coupling: To a mixture of the acid(0.060 g, 0.11 mmol) and a secondary/tertiary amine containing diaminebishydrochloric acid salt (0.034 g, 0.17 mmol) in DMC (1.5 mL) was addedEt₃N (0.096 mL, 0.69 mmol) and HBTU (0.065 g, 0.17 mmol). The mixturewas stirred at room temperature for 0.5 h, diluted with MeOH, removedthe solvent. The residue was dissolved in methanol, filtered, andpurified by prep-HPLC to afford A TFA salt of an amide 1 (0.0378 g, 82%)as TFA salt which was characterized by LC-MS and 1H NMR.

The product was prepared from the acid (0.47 g, 44%). LC-MS retentiontime: 3.54; MS m/z 551 (M+H).

The product was prepared (0.43 g, 94%). LC-MS retention time: 3.49; MSm/z 537 (M+H).

The product was prepared from the acid (0.96 g, 59%). LC-MS retentiontime: 3.58; MS m/z 578 (M+H). compound was observed to exist asinter-converting rotamers (3/4). The major isomer: ¹H NMR (400 MHz,CHLOROFORM-D) δ ppm 1.16-1.59 (m, 4H), 1.72 (dd, J=9.44, 4.15 Hz, 3H),1.88-2.12 (m, 4H), 2.24-2.36 (m, 2H), 2.75-2.97 (m, 2H), 3.44 (d,J=14.86 Hz, 1H), 3.56 (s, 3H), 3.89 (s, 3H), 4.09 (d, 1H), 4.24-4.37 (m,4H), 5.41 (d, J=14.86 Hz, 1H), 6.92-6.96 (m, 1H), 7.13 (d, J=2.01 Hz,1H), 7.24-7.30 (m, 1H), 7.39 (dd, J=8.31, 1.51 Hz, 1H), 7.84-7.88 (m,1H), 8.24 (d, J=1.51 Hz, 1H).

The product was prepared (0.93 g, 100%). LC-MS retention time: 3.51; MSm/z 564 (M+H). Compound was observed to exist as inter-convertingrotamers (˜3/4). The major isomer: ¹H NMR (400 MHz) ppm 0.34-0.42 (m,1H), 1.15-2.10 (m, 11H), 2.22-2.38 (m, 2H), 2.65-2.78 (m, 1H), 2.84-2.94(m, J=3.02 Hz, 1H), 3.84 (s, 3H), 4.03 (d, J=15.11 Hz, 1H), 4.21-4.43(m, 4H), 5.34 (d, J=14.86 Hz, 1H), 6.87 (dd, J=8.56, 2.77 Hz, 1H), 6.98(d, J=2.52 Hz, 1H), 7.21 (d, J=8.31 Hz, 1H), 7.69-7.75 (m, 1H),7.86-7.90 (m, 1H), 8.13 (s, 1H).

The product was prepared from the acid (0.109 g, 67%). LC-MS retentiontime: 3.60; MS m/z 580 (M+H). Compound was observed to exist asinter-converting rotamers (˜5/4). The major isomer: ¹H NMR (400 MHz) ppm1.16-2.09 (m, 14H), 2.73-2.93 (m, 2H), 3.07 (s, 3H), 3.31-3.52 (m, 3H),3.76 (s, 3H), 3.88 (s, 3H), 4.05-4.10 (m, 1H), 5.40 (d, J=15.11 Hz, 1H),6.88-6.93 (m, 1H), 7.13 (d, J=2.27 Hz, 1H), 7.22-7.29 (m, 1H), 7.33-7.42(m, 1H), 7.82-7.86 (m, 1H), 8.19 (d, J=1.51 Hz, 1H).

The product was prepared (0.108 g, 100%). LC-MS retention time: 3.55; MSm/z 566 (M+H).

The product was prepared from the acid (0.127 g, 67%). LC-MS retentiontime: 3.64; MS m/z 594 (M+H). Compound was observed to exist asinter-converting rotamers: ¹H NMR (400 MHz) ppm 1.11-2.13 (m, 18H), 2.64(dd, J=10.07, 6.80 Hz, 1H), 2.84-2.96 (m, 1H), 3.34-3.67 (m, 4H), 3.75(s, 3H), 3.88 (s, 3H), 4.03-4.10 (m, 1H), 5.40 (d, J=15.36 Hz, 1H),6.90-6.95 (m, 1H), 7.13 (d, J=2.01 Hz, 1H), 7.21-7.29 (m, 1H), 7.33-7.39(m, 1H), 7.83 (d, J=8.06 Hz, 1H), 8.20 (d, J=1.26 Hz, 1H).

The product was prepared (0.126 g, 100%). LC-MS retention time: 3.57; MSm/z 580 (M+H).

Example 1

tert-butyl7-((8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl)carbonyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate.HATU (54 mg, 0.14 mmol) was added to a stirring solution of8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (60 mg, 0.11 mmol) and tert-butyl2,7-diazaspiro[4.4]nonane-2-carboxylate (74 mg, 0.33 mmol) in DMF (1 mL)and TEA (0.09 mL, 0.7 mmol). The reaction was stirred for 30 min (˜80%conversion by LCMS) and additional tert-butyl2,7-diazaspiro[4.4]nonane-2-carboxylate (˜25 mg) and HATU (˜20 mg) wereadded. The reaction was stirred for 20 min (complete by LCMS), dilutedwith MeOH (2 mL), filtered and purified by preparative HPLC (CH₃CN/H₂Owith 10 mM NH₄OAc) to yield tert-butyl7-((8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl)carbonyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate(59.5 mg, 0.078 mmol, 72.0% yield) as an off-white solid. The compoundwas isolated as a mixture of four stereoisomers and presents as a ˜1:4mixture of rotamers or atrope isomers. ¹HNMR (300 MHz, CD₃OD) δ0.12-3.71 (m, 42H), 3.91 (s, 3H), 3.89-4.05 (m, 1H), 5.10-5.23 (m, 1H),6.97-7.07 (m, 1H), 7.21 (d, J=2.2 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.68(br d, J=8.4 Hz, 1H), 7.85-7.95 (m, 1H). 7.99-8.33 (m, 1H). LC-MSretention time: 3.86 min; m/z 759 (MH+). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 10% MeOH/90% H₂O/0.1%trifluoroacetic acid and solvent B was 10% H₂O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a Micromass Platformfor LC in electrospray mode.

Example 2

8-Cyclohexyl-1a-(2,7-diazaspiro[4.4]non-2-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.tert-Butyl7-((8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl)carbonyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate(49 mg, 0.065 mmol) was dissolved into DCE (1 mL) and then TFA (0.200mL, 2.60 mmol) was added and the reaction was stirred at rt for 2 h(complete by LCMS). The reaction was concentrated with a stream ofnitrogen and dried under high vacuum at 60 C. for 5 h to yield8-cyclohexyl-1a-(2,7-diazaspiro[4.4]non-2-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamideTFA (51.0 mg, 0.066 mmol, quant.) as a yellow solid. The compound wasisolated as a mixture of four stereoisomers and presents as a ˜1:9mixture of rotamers or atrope isomers (major is reported). ¹HNMR (300MHz, CD₃OD) δ 1.11-3.49 (m, 31H), 3.54-7.72 (m, 2H), 3.91 (s, 3H),3.95-4.06 (m, 1H), 5.19 (d, J=15.0 Hz, 1H), 7.05 (dd, J=8.8, 2.6 Hz,1H), 7.22 (d, J=2.6 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.61 (dd, J=8.4,1.5 Hz, 1H), 7.91-8.00 (m, 2H). LC-MS retention time: 3.17 min; m/z 659(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 5 mL/min, a gradient of 100%solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient timeof 4 min, a hold time of 1 min, and an analysis time of 5 min wheresolvent A was 10% MeOH/90% H₂O/0.1% trifluoroacetic acid and solvent Bwas 10% H₂O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a Micromass Platform for LC in electrospray mode.

Example 3

8-Cyclohexyl-N-(cyclopropylsulfonyl)-11-methoxy-1a-((2-methyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.HATU (27 mg, 0.071 mmol) was added to a stirring solution of8-cyclohexyl-5-((cyclopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (30 mg, 0.055 mmol) and 2-methyl-2,7-diazaspiro[4.5]decan-1-one,HCl (18 mg, 0.088 mmol) in DMF (0.5 mL) and TEA (0.05 mL, 0.3 mmol). Thereaction mixture was stirred for 1 h, diluted with MeOH (˜1 mL) andpurified by preparative HPLC (CH₃CN/H₂O with 10 mM NH₄OAc) to yield thefirst eluting diastereomer ofcyclohexyl-N-(cyclopropylsulfonyl)-11-methoxy-1a-((2-methyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(26.2 mg, 0.038 mmol, 68%) as an off-white solid and the second elutingdiastereomer (11.0 mg, 0.016 mmol, 29%) as an off-white solid. Firsteluting diastereomer: The compound was isolated as a racemic mixture andpresents as a ˜1:9 mixture of rotamers or atrope isomers (major isreported). 1HNMR (300 MHz, CD3OD) δ 0.85-3.34 (m, 30H), 2.79 (s, 3H),3.67 (d, J=15.0 Hz, 1H), 3.90 (s, 3H), 4.09 (d, J=13.5 Hz, 1H), 5.21 (d,J=15.0 Hz, 1H), 7.03 (dd, J=8.8, 2.6 Hz, 1H), 7.19 (d, J=2.6 Hz, 1H),7.33 (d, J=8.8 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H),8.12 (s, 1H). LC-MS retention time: 2.30 min; m/z 697 (MH−). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPhenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 mL/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode. Second elutingdiastereomer: The compound was isolated as a racemic mixture andpresents as a ˜1:2 mixture of rotamers or atrope isomers. 1HNMR (300MHz, CD3OD) δ 0.19-0.25 (m, 0.33H), 1.02-3.44 (m, 31.67H), 3.63-3.74 (m,1.33H), 3.90 (s, 2H), 3.92 (s, 1H), 3.95-4.20 (m, 2H), 5.06 (d, J=15.0Hz, 0.67H), 6.96-7.04 (m, 1H), 7.11-7.21 (m, 1H), 7.27-7.38 (m, 1H),7.65 (d, J=8.8 Hz, 0.67H), 7.70 (d, J=8.4 Hz, 0.33H), 7.82-7.91 (m, 1H),8.03-8.19 (m, 1H). LC-MS retention time: 2.34 min; m/z 697 (MH−). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 mL/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

Example 4

8-Cyclohexyl-N-(isopropylsulfonyl)-11-methoxy-1a-((2-methyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.HATU (30 mg, 0.08 mmol) was added to a stirring solution of8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (33 mg, 0.060 mmol) and 2-methyl-2,7-diazaspiro[4.5]decan-1-one,HCl (18 mg, 0.088 mmol) in DMF (0.5 mL) and TEA (0.05 mL, 0.3 mmol). Thereaction mixture was stirred for 1 h, diluted with MeOH (˜1 mL) andpurified by preparative HPLC (CH₃CN/H₂O with 10 mM NH₄OAc) to yield thefirst eluting racemic diastereomer of8-cyclohexyl-N-(isopropylsulfonyl)-11-methoxy-1a-((2-methyl-1-oxo-2,7-diazaspiro[4.5]dec-7-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(29.0 mg, 0.041 mmol, 69%) as an off-white solid and the second elutingdiastereomer (7.5 mg, 0.011 mmol, 18%) as an off-white solid. Firsteluting racemic diastereomer: The compound was isolated as a racemicmixture and presents as a ˜1:4 mixture of rotamers or atrope isomers.¹HNMR (300 MHz, CD₃OD) δ 0.16-0.29 (m, 0.2H), 0.84-3.44 (m, 30.8H), 2.79(s, 3H), 3.67 (d, J=15.4 Hz, 1H), 3.90 (s, 2.4H), 3.92 (s, 0.6H),3.86-3.97 (m, 1H), 4.01-4.16 (m, 1H), 4.89-5.10 (m, 0.2H), 5.20 (d,J=15.4 Hz, 0.8H), 6.95-7.02 (m, 0.2H), 7.02 (dd, J=8.4, 2.6 Hz, 0.8H),7.16-7.20 (m, 1H), 7.32 (d, J=8.4 Hz, 0.2H), 7.33 (d, J=8.4 Hz, 0.8H),7.69-7.77 (m, 1H), 7.84 (d, J=8.8 Hz, 1H), 8.12 (s, 0.8H), 8.24 (s,0.2H). LC-MS retention time: 2.36 min; m/z 699 (MH−). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPhenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 mL/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where solvent A was 5%acetonitrile/95% H₂O/10 mM ammonium acetate and solvent B was 5% H₂O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode. Seconds eluting racemicdiastereomer: The compound was isolated as a racemic mixture andpresents as a ˜1:2 mixture of rotamers or atrope isomers. ¹HNMR (300MHz, CD₃OD) δ 0.16-0.24 (m, 0.33H), 1.05-3.73 (m, 33.67H), 3.90 (s, 2H),3.92 (s, 1H), 3.88-4.24 (m, 3H), 4.87-4.96 (m, 0.33H), 5.07 (d, J=15.4Hz, 0.67H), 7.02 (dd, J=8.4. 1.8 Hz, 1H), 7.16 (br s, 0.33H), 7.20 (d,J=1.8 Hz, 0.67H), 7.32 (d, J=8.4 Hz, 0.67H), 7.35 (d, J=8.4 Hz, 0.33H),7.62 (d, J=8.4 Hz, 0.67H), 7.67 (d, J=8.4 Hz, 0.33H), 7.89 (d, J=8.4 Hz,0.67H), 7.91 (d, J=8.4 Hz, 0.33H), 8.07 (s, 0.33H), 8.14 (s, 0.67H).LC-MS retention time: 2.45 min; m/z 699 (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 5% acetonitrile/95% H₂O/10 mMammonium acetate and solvent B was 5% H₂O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

Example 5

8-Cyclohexyl-N-(isopropylsulfonyl)-11-methoxy-1a-((2-methyl-2,7-diazaspiro[4.5]dec-7-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.LiAlH₄ (80 mg, 2.1 mmol) was added as a solid (exothermic and foamingoccurred) to a slurry of 2-methyl-2,7-diazaspiro[4.5]decan-1-one, HCl(160 mg, 0.78 mmol) in THF (3 mL) and the reaction was stirred 1 h atrt, and then 1 h at 60° C. The reaction mixture was cooled to rt andthen slowly quenched with H₂O (˜3 mL) and 1M NaOH (0.5 mL) and stirredON. The resulting emulsion was diluted with DCM (˜20 mL) and filteredthrough celite (flushing with DCM) and the layers were separated. Theorganic layers was dried (MgSO₄), filtered and concentrated to yield2-methyl-2,7-diazaspiro[4.5]decane (˜70 mg. 0.45 mmol, 60%) as a clearcolorless oil, which was used without further purification.2-Methyl-2,7-diazaspiro[4.5]decane (˜70 mg. 0.45 mmol) was dissolvedinto DMF (1 mL) and 1/2 of this solution (0.5 mL) was added to8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (30 mg, 0.054 mmol). The reaction solution was then treated withTEA (100 μL, 0.72 mmol) and HATU (30 mg, 0.079 mmol) and stirred 1 h(complete by LCMS). The reaction was diluted with MeOH (1 mL) andpurified by preparative HPLC (CH₃CN/H₂O with 10 mM NH₄OAc) in oneinjection to yield the first eluting racemic diastereomer of8-cyclohexyl-N-(isopropylsulfonyl)-11-methoxy-1a-((2-methyl-2,7-diazaspiro[4.5]dec-7-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(16.5 mg, 0.024 mmol, 44%) as a white solid and the second elutingracemic diastereomer (14.0 mg, 0.020 mmol, 38%) as a white solid. Eachcompound was isolated as a racemic mixture. First eluting racemicdiastereomer: ¹HNMR (300 MHz, CDCl₃) δ ppm 1.23-2.24 (m, 24H), 2.57-2.66(m, 1H), 2.74 (s, 3H), 2.74-3.59 (m, 9H), 3.64 (d, J=15.0 Hz, 1H), 3.90(s, 3H), 3.83-3.97 (m, 1H), 5.11 (d, J=15.0 Hz, 1H), 7.00 (dd, J=8.8,2.6 Hz, 1H), 7.18 (d, J=2.6 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.73 (d,J=8.4 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 8.19 (s, 1H). LC-MS retentiontime: 2.50 min; m/z 685 (MH−). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 5% acetonitrile/95% H₂O/10 mMammonium acetate and solvent B was 5% H₂O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. Second eluting racemic diastereomer: Presentsas a ˜1:2 mixture of rotamers or atrope isomers. ¹HNMR (300 MHz, CD₃OD)δ 0.74-2.24 (m, 24H), 2.45-3.25 (m, 9H), 3.50-3.77 (m, 1.33H), 3.84-3.95(m, 1.67H), 3.91 (s, 3H), 5.05-5.25 (m, 1H), 6.96-7.06 (m, 1H), 7.18 (d,J=2.6 Hz, 1H), 7.31 (d, J=8.4 Hz, 0.67H), 7.34 (d, J=8.4 Hz, 0.33H),7.71-7.83 (m, 2H), 8.13 (s, 0.33H), 8.20 (s, 0.67H). LC-MS retentiontime: 2.56 min; m/z 685 (MH−). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 5% acetonitrile/95% H₂O/10 mMammonium acetate and solvent B was 5% H₂O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

Example 6

8-Cyclohexyl-11-methoxy-1a-((2-methyl-2,7-diazaspiro[4.5]dec-7-yl)carbonyl)-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.LiAlH₄ (80 mg, 2.1 mmol) was added as a solid (exothermic and foamingoccurred) to a slurry of 2-methyl-2,7-diazaspiro[4.5]decan-1-one, HCl(160 mg, 0.782 mmol) in THF (3 mL) and the reaction was stirred 1 h atrt, and then 1 h at 60° C. The reaction mixture was cooled to rt andthen slowly quenched with H₂O (˜3 mL) and 1M NaOH (0.5 mL) and stirredON. The resulting emulsion was diluted with DCM (˜20 mL) and filteredthrough celite (flushing with DCM) and the layers were separated. Theorganic layers was dried (MgSO₄), filtered and concentrated to yield2-methyl-2,7-diazaspiro[4.5]decane (˜70 mg. 0.45 mmol, 60%) as a clearcolorless oil, which was used without further purification.2-Methyl-2,7-diazaspiro[4.5]decane (˜70 mg. 0.45 mmol) was dissolvedinto DMF (1 mL) and 1/2 of this solution (0.5 mL) was added to8-cyclohexyl-11-methoxy-5-((propylsulfonyl)carbamoyl)-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (32 mg, 0.058 mmol). The reaction solution was then treated withTEA (100 μL, 0.717 mmol) and HATU (30 mg, 0.079 mmol) and stirred 1 h(complete by LCMS). The reaction was diluted with MeOH (1 mL) andpurified by preparative HPLC (CH₃CN/H₂O with 10 mM NH₄OAc) in oneinjection to yield the first eluting diastereomer of8-cyclohexyl-11-methoxy-1a-((2-methyl-2,7-diazaspiro[4.5]dec-7-yl)carbonyl)-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(16.3 mg, 0.023 mmol, 40%) as a white solid and the second elutingracemic diastereomer (15.8 mg, 0.023 mmol, 40%) as a white solid. Eachcompound was isolated as a racemic mixture. First eluting racemicdiastereomer: ¹HNMR (300 MHz, CD₃OD) δ ppm 1.10 (t, J=7.3 Hz, 3H),1.20-2.23 (m, 21H), 2.57-2.65 (m, 1H), 2.74 (s, 3H), 2.75-3.51 (m, 10H),3.64 (d, J=15.0 Hz, 1H), 3.90 (s, 3H), 5.11 (d, J=15.0 Hz, 1H), 7.00 (brd, J=8.4 Hz, 1H), 7.15 (br s, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.74 (d,J=8.4 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 8.18 (s, 1H). LC-MS retentiontime: 2.51 min; m/z 685 (MH−). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 5% acetonitrile/95% H₂O/10 mMammonium acetate and solvent B was 5% H₂O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. Second eluting racemic diastereomer: Presentsas a 1:2 mixture of rotamers or atrope isomers. ¹HNMR (300 MHz, CD₃OD) δppm 0.84-3.42 (m, 37H), 3.52-3.72 (m, 1H), 3.90 (s, 3H), 4.39-4.65 (m,1H), 5.03-5.25 (m, 1H), 6.95-7.06 (m, 1H), 7.18 (br s, 1H), 7.26-7.37(m, 1H), 7.70-7.84 (m, 2H), 8.13 (s, 0.33H), 8.20 (s, 0.67H). LC-MSretention time: 2.55 min; m/z 685 (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 5% acetonitrile/95% H₂O/10 mMammonium acetate and solvent B was 5% H₂O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

Example 7

tert-Butyl8-((8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,2b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl)carbonyl)-1,8-diazaspiro[4.5]decane-1-carboxylate.HATU (72 mg, 0.19 mmol) was added to a stirring solution of8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (80 mg, 0.145 mmol) and tert-butyl1,8-diazaspiro[4.5]decane-1-carboxylate, HCl (64 mg, 0.23 mmol) in DMF(1.2 mL) and TEA (250 μL, 1.79 mmol) and the reaction mixture wasstirred at rt for 1 h (complete by LCMS). The reaction mixture wasdiluted with MeOH (1.8 mL) and purified by preparative HPLC (CH₃CN/H₂Owith 10 mM NH₄OAc) in two injections. The fractions containing thedesired product were combined and concentrated to remove the CH₃CN. Theremaining turbid aqueous layer was extracted with EtOAc (2×50 mL) andthe combined organic layers were dried (MgSO₄) filtered and concentratedto yield tert-butyl8-((8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl)carbonyl)-1,8-diazaspiro[4.5]decane-1-carboxylate(95 mg, 0.12 mmol, 85% yield) as a yellow solid. The compound wasisolated as a mixture of enantiomers and presents as a 1:1 mixture orrotamers or atrope isomers. ¹HNMR (300 MHz, CD₃OD) δ ppm 0.12-0.22 (m,0.5H), 0.85-0.96 (m, 1.5H), 1.03-3.12 (m, 37H), 3.35-3.59 (m, 2.5H),3.65 (d, J=15.0 Hz, 0.5H), 3.91 (s, 1.5H), 3.92 (s, 1.5H), 4.00 (p,J=6.8 Hz, 1H), 4.09-4.48 (m, 2H), 5.08 (d, J=15.0 Hz, 0.5H), 6.98-7.06(m, 1H), 7.18 (br s, 0.5H), 7.22 (d, J=2.2 Hz, 0.5H), 7.34 (d, J=8.4 Hz,0.5H), 7.36 (d, J=8.8 Hz, 0.5H), 7.57-7.68 (m, 0.5H), 7.87-7.97 (m,1.5H), 8.06-8.20 (m, 0.5H). LC-MS retention time: 3.05 min; m/z 771(MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 5 mL/min, a gradient of 100%solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient timeof 4 min, a hold time of 1 min, and an analysis time of 5 min wheresolvent A was 5% acetonitrile/95% H₂O/10 mM ammonium acetate and solventB was 5% H₂O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.

Example 8

tert-Butyl8-((8-cyclohexyl-11-methoxy-5-((propylsulfonyl)carbamoyl)-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl)carbonyl)-1,8-diazaspiro[4.5]decane-1-carboxylate.8-Cyclohexyl-11-methoxy-5-((propylsulfonyl)carbamoyl)-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (80 mg, 0.145 mmol) and tert-butyl1,8-diazaspiro[4.5]decane-1-carboxylate, HCl (64.3 mg, 0.232 mmol) wereslurried into DMF (1.2 mL) and TEA (250 μL, 1.794 mmol). HATU (71.8 mg,0.189 mmol) was added and the reaction mixture was stirred at rt for 1 h(complete by LCMS). The reaction mixture was diluted with MeOH (1.8 mL)and purified by preparative HPLC (CH₃CN/H₂O with 10 mM NH₄OAc) in twoinjections. The fractions containing the desired product were combinedand concentrated to remove the CH₃CN. The remaining turbid aqueous layerwas extracted with EtOAc (2×50 mL) and the combined organic layers weredried (MgSO₄) filtered and concentrated to yield tert-butyl8-((8-cyclohexyl-11-methoxy-5-((propylsulfonyl)carbamoyl)-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl)carbonyl)-1,8-diazaspiro[4.5]decane-1-carboxylate(88 mg, 0.11 mmol, 78% yield) as a yellow solid. The compound wasisolated as a mixture of enantiomers and presents as a ˜1:1 mixture orrotamers or atrope isomers. ¹HNMR (300 MHz, CD₃OD) δ ppm 0.14-0.24 (m,0.5H), 0.87-3.15 (m, 24.5H), 1.12 (t, J=7.5 Hz, 3H), 1.43 (s, 9H),3.35-3.70 (m, 6H), 3.91 (s, 1.5H), 3.92 (s, 1.5H), 4.11-4.65 (m, 2H),4.88-4.94 (m, 0.5H), 5.08 (d, J=15.0 Hz, 0.5H), 6.99-7.07 (m, 1H),7.15-7.20 (m, 0.5H), 7.22 (d, J=2.2 Hz, 0.5H), 7.34 (d, J=8.4 Hz, 0.5H),7.36 (d, J=8.4 Hz, 0.5H), 7.57-7.68 (m, 1H), 7.87-7.96 (m, 1.5H),8.05-8.19 (m, 0.5H). LC-MS retention time: 2.99 min; m/z 771 (MH−). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 mL/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where solvent A was 5%acetonitrile/95% H₂O/10 mM ammonium acetate and solvent B was 5% H₂O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

Example 9

8-cyclohexyl-1a-(1,8-diazaspiro[4.5]dec-8-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.tert-Butyl8-((8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl)carbonyl)-1,8-diazaspiro[4.5]decane-1-carboxylate(83 mg, 0.107 mmol) was dissolved into 1,2-dichloroethane (2 mL) andthen TFA (1 mL, 13 mmol) was added (solution became bright yellow). Thereaction was stirred for 2 h (complete by LCMS), concentrated, dilutedwith MeOH, filtered and purified by preparative HPLC (CH₃CN/H₂O withNH₄OAc buffer) in two injections to yield8-cyclohexyl-1a-(1,8-diazaspiro[4.5]dec-8-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(48.3 mg, 0.072 mmol, 66% yield) as an off-white solid. The compound wasisolated as a mixture of enantiomers. ¹HNMR (300 MHz, CDCl₃) δ ppm0.63-2.41 (m, 31H), 2.53-3.33 (m, 5H), 3.51-3.66 (m, 1H), 3.77-3.90 (m,1H), 3.86 (s, 3H), 4.01-4.15 (m, 1H), 4.09-4.48 (m, 2H), 6.83-6.96 (m,2H), 6.96-7.06 (m, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.71-7.88 (m, 1H), 7.99(s, 1H). LC-MS retention time: 2.42 min; m/z 671 (MH−). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPhenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 mL/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where solvent A was 5%acetonitrile/95% H₂O/10 mM ammonium acetate and solvent B was 5% H₂O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

Example 10

8-cyclohexyl-1a-(1,8-diazaspiro[4.5]dec-8-ylcarbonyl)-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.tert-Butyl8-((8-cyclohexyl-11-methoxy-5-((propylsulfonyl)carbamoyl)-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepin-1a(2H)-yl)carbonyl)-1,8-diazaspiro[4.5]decane-1-carboxylate(76 mg, 0.098 mmol) was dissolved into 1,2-dichloroethane (2 mL) andthen TFA (1 mL, 12.98 mmol) was added (solution became bright yellow).The reaction was stirred for 2 h (complete by LCMS), concentrated,diluted with MeOH, filtered and purified by preparative HPLC (CH₃CN/H₂Owith NH₄OAc buffer) in two injections to yield8-cyclohexyl-1a-(1,8-diazaspiro[4.5]dec-8-ylcarbonyl)-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(53.9 mg, 0.080 mmol, 81% yield) as an off-white solid. The compound wasisolated as a mixture of enantiomers. ¹HNMR (300 MHz, CDCl₃) δ ppm0.24-0.35 (m, 0.15H), 0.61-3.63 (m, XXH), 3.86 (s, 3H), 3.98-4.57 (m,3H), 6.83-6.96 (m, 2H), 6.96-7.08 (m, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.77(br s, 1H), 7.98 (s, 1H), 8.18-8.97 (m, 1H). LC-MS retention time: 2.42min; m/z 671 (MH−). LC data was recorded on a Shimadzu LC-1 OAS liquidchromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 mL/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min wheresolvent A was 5% acetonitrile/95% H₂O/10 mM ammonium acetate and solventB was 5% H₂O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.

Example 11

8-Cyclohexyl-N-(isopropylsulfonyl)-11-methoxy-1a-((1-methyl-1,8-diazaspiro[4.5]dec-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.Formaldehyde (37% in water, 50 μL, 0.62 mmol) was added to a stirringsolution of8-cyclohexyl-1a-(1,8-diazaspiro[4.5]dec-8-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(19.3 mg, 0.029 mmol) in DCM (0.5 mL) and acetic acid (0.1 mL). Thesolution was then treated with sodium cyanoborohydride (15 mg, 0.24mmol) (foaming occurred) and stirred 2 h. The reaction was concentratedunder a stream of nitrogen and the residue was dissolved into MeOH (1.5mL), filtered and purified by preparative HPLC (CH₃CN/H₂O with 10 mMNH₄OAc) to yield8-cyclohexyl-N-(isopropylsulfonyl)-1′-methoxy-1a-((1-methyl-1,8-diazaspiro[4.5]dec-8-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(11.5 mg, 0.017 mmol, 58% yield) as an off-white solid. The compound wasisolated as a mixture of enantiomers and presents as a ˜1:1 mixture orrotamers or atrope isomers. ¹HNMR (300 MHz, CD₃OD) δ ppm 0.27-0.34 (m,0.5H), 0.94-1.04 (m, 0.5H), 1.19-3.17 (m, 33H), 3.53-3.85 (m, 2.5H),3.90 (s, 1.5H), 3.92 (s, 1.5H), 3.90-4.00 (m, 1H), 4.12-4.20 (m, 0.5H),4.33-4.57 (m, 1H), 4.87-4.96 (m, 0.5H), 5.08-5.18 (m, 0.5H), 6.95-7.04(m, 1H), 7.18 (d, J=2.6 Hz, 0.5H), 7.19 (d, J=2.6 Hz, 0.5H), 7.32 (d,J=8.8 Hz, 0.5H), 7.34 (d, J=8.4 Hz, 0.5H), 7.72-7.85 (m, 2H), 8.19 (s,0.5H), 8.28 (s, 0.5H). LC-MS retention time: 2.31 min; m/z 685 (MH−). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 mL/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where solvent A was 5%acetonitrile/95% H₂O/10 mM ammonium acetate and solvent B was 5% H₂O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

Example 12

8-Cyclohexyl-11-methoxy-1a-((1-methyl-1,8-diazaspiro[4.5]dec-8-yl)carbonyl)-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.Formaldehyde (37% in water, 100 μL, 1.23 mmol) was added to a stirringsolution of8-cyclohexyl-1a-(1,8-diazaspiro[4.5]dec-8-ylcarbonyl)-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(24.5 mg, 0.036 mmol) in DCM (0.5 mL) and acetic acid (0.1 mL). Thesolution was then treated with sodium cyanoborohydride (15 mg, 0.24mmol) (foaming occurred) and stirred 2 h. The reaction was concentratedunder a stream of nitrogen and the residue was dissolved into MeOH,filtered and purified by preparative HPLC (CH₃CN/H₂O with 10 mM NH₄OAc)to yield8-cyclohexyl-11-methoxy-1a-((1-methyl-1,8-diazaspiro[4.5]dec-8-yl)carbonyl)-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(18.8 mg, 0.027 mmol, 75% yield) as an off-white solid. The compound wasisolated as a mixture of enantiomers. LC-MS retention time: 3.12 min;m/z 687 (MH+). The compound was isolated as a mixture of enantiomers andpresents as a 4:6 mixture of atrope isomers or rotamers. ¹HNMR (300 MHz,CD₃OD) δ 0.23-0.36 (m, 0.4H), 0.91-1.00 (m, 0.6H), 1.09 (t, J=7.5 Hz,3H), 1.17-3.06 (m, 29H), 3.28-3.86 (m, 4H), 3.89 (s, 1.8H), 3.91 (s,1.2H), 4.66-5.20 (m, 3H), 6.97 (dd, J=8.4, 2.6 Hz, 0.4H), 6.97 (dd,J=8.4, 2.6 Hz, 0.6H), 7.16 (d, J=8.4 Hz, 0.6H), 7.18 (d, J=8.4 Hz,0.4H), 7.28 (d, J=8.8 Hz, 0.6H), 7.30 (d, J=8.4 Hz, 0.4H), 7.77-7.84 (m,2H), 8.15 (br s, 0.6H), 8.26 (br s, 0.4H). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10μ C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 10% MeOH/90% H₂O/0.1%trifluoroacetic acid and solvent B was 10% H₂O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a Micromass Platformfor LC in electrospray mode.

8-methyl-1,8-diazaspiro[4.5]decane. tert-Butyl1,8-diazaspiro[4.5]decane-1-carboxylate, HCl (150 mg, 0.542 mmol) wasdissolved into MeOH (2.5 mL), neutralized with 1M NaOH aq. (0.50 mL) andtreated with formalin (1.3 mL) and then sodium cyanoborohydride (51 mg,0.81 mmol). The reaction was stirred at rt for 4 h, partitioned betweenEtOAc and water and the organic layer was concentrated to dryness. Theresidue was dissolved into DCE (1 mL) and TFA (1 mL) was then added. Thereaction was stirred 3 h and concentrated to dryness under vacuum toyield-methyl-1,8-diazaspiro[4.5]decane as a yellow oil which was usedwithout further purification.

Example 13

13-Cyclohexyl-N-(isopropylsulfonyl)-3-methoxy-6-((8-methyl-1,8-diazaspiro[4.5]dec-1-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide.HATU (30 mg, 0.079 mmol) was added to a stirring solution of13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylicacid (34 mg, 0.063 mmol) and 8-methyl-1,8-diazaspiro[4.5]decane (24 mg,0.16 mmol) in DMF (0.5 mL) and TEA (100 μL, 0.72 mmol) and the reactionmixture was stirred at rt for 1 h (complete by LCMS). The reactionmixture was diluted with MeOH, filtered and purified by preparative HPLC(CH₃CN/H₂O w/10 mM NH₄OAc) to yield13-cyclohexyl-N-(isopropylsulfonyl)-3-methoxy-6-((8-methyl-1,8-diazaspiro[4.5]dec-1-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide(19.7 mg, 0.029 mmol, 46% yield) as a yellow solid. ¹HNMR (300 MHz,CD₃OD) δ ppm 1.10-2.20 (m, 22H), 2.76 (s, 3H), 2.67-3.49 (m, 9H), 3.91(s, 3H), 3.86-4.00 (m, 1H), 4.27-4.45 (m, 1H), 5.07-5.20 (m, 1H), 6.91(s, 1H), 7.03 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.8, 2.6 Hz, 1H), 7.56 (d,J=8.8 Hz, 1H), 7.73 (dd, J=8.4, 1.5 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H),8.26 (br s, 1H). LC-MS retention time: 2.64 min; m/z 671 (MH−). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPhenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 mL/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where solvent A was 5%acetonitrile/95% H₂O/10 mM ammonium acetate and solvent B was 5% H₂O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

Example 14

8-Cyclohexyl-N-(isopropylsulfonyl)-1-methoxy-1a-((8-methyl-1,8-diazaspiro[4.5]dec-1-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.8-Cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (31 mg, 0.056 mmol) and 8-methyl-1,8-diazaspiro[4.5]decane (19 mg,0.12 mmol) were dissolved into DMF (0.5 mL) and TEA (100 μL, 0.72 mmol)and stirred. HATU (30 mg, 0.079 mmol) was added and the reaction mixturewas stirred at rt for 1 h (complete by LCMS). The reaction mixture wasdiluted with MeOH, filtered and purified by preparative HPLC (CH₃CN/H₂Ow/10 mM NH₄OAc) to yield8-cyclohexyl-N-(isopropylsulfonyl)-11-methoxy-1a-((8-methyl-1,8-diazaspiro[4.5]dec-1-yl)carbonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(16.4 mg, 0.024 mmol, 42% yield) as an off-white solid. The compound wasisolated as a mixture of enantiomers. ¹HNMR (300 MHz, CD₃OD) δ 0.77-2.23(m, 27H), 2.63-3.11 (m, 5H), 2.77 (s, 3H), 3.60 (d, J=15.4 Hz, 1H),3.42-3.67 (m, 2H), 3.89 (s, 3H), 3.87-4.00 (m, 1H), 5.17 (d, J=15.4 Hz,1H), 7.01 (dd, J=8.4, 2.6 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.33 (d,J=8.4 Hz, 1H), 7.70 (dd, J=8.4, 1.1 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H),8.15 (br s, 1H). LC-MS retention time: 2.51 min; m/z 685 (MH−). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPhenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 mL/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where solvent A was 5%acetonitrile/95% H₂O/10 mM ammonium acetate and solvent B was 5% H₂O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

Example 15

8-Cyclohexyl-11-methoxy-1a-((8-methyl-1,8-diazaspiro[4.5]dec-1-yl)carbonyl)-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.HATU (30 mg, 0.079 mmol) was added to a stirring solution of8-cyclohexyl-11-methoxy-5-((propylsulfonyl)carbamoyl)-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (30 mg, 0.054 mmol) and 8-methyl-1,8-diazaspiro[4.5]decane (17 mg,0.11 mmol) in DMF (0.5 mL) and TEA (100 μL, 0.72 mmol) and the reactionmixture was stirred at rt for 1 h (complete by LCMS). The reactionmixture was diluted with MeOH, filtered and purified by preparative HPLC(CH₃CN/H₂O w/10 mM NH₄OAc) to yield8-cyclohexyl-11-methoxy-1a-((8-methyl-1,8-diazaspiro[4.5]dec-1-yl)carbonyl)-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(16.7 mg, 0.024 mmol, 45% yield) as an off-white solid. The compound wasisolated as a mixture of enantiomers and presented as a mixture ofatrope isomers or rotamers. Partial ¹HNMR (300 MHz, CD₃OD) δ 2.77 (s,3H), 3.90 (s, 3H), 6.96-7.04 (m, 1H), 7.15-7.21 (m, 1H), 7.31 (d, J=8.8Hz, 0.4H), 7.33 (d, J=8.4 Hz, 0.6H), 7.66-7.85 (m, 2H), 8.04-8.23 (m,1H). LC-MS retention time: 2.53 min; m/z 685 (MH−). LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with aPhenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 mL/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where solvent A was 5%acetonitrile/95% H₂O/10 mM ammonium acetate and solvent B was 5% H₂O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

Example 16

1a-((1-Acetyl-1,8-diazaspiro[4.5]dec-8-yl)carbonyl)-8-cyclohexyl-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.8-Cyclohexyl-1a-(1,8-diazaspiro[4.5]dec-8-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(15.2 mg, 0.023 mmol) and acetic acid (11 mg, 0.18 mmol) were dissolvedinto DMF (0.4 mL) and TEA (75 μL, 0.538 mmol) and stirred. HATU (19 mg,0.050 mmol) was added and the reaction mixture was stirred at rt for 2 h(complete by LCMS). The reaction mixture was diluted with MeOH, filteredand purified by preparative HPLC (CH3CN/H2O w/10 mM NH4OAc) to yield1a-((1-acetyl-1,8-diazaspiro[4.5]dec-8-yl)carbonyl)-8-cyclohexyl-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(15.0 mg, 0.021 mmol, 93% yield) as an off-white solid. The compound wasisolated as a mixture of enantiomers and presents as a ˜1:1 mixture orrotamers or atrope isomers. 1HNMR (300 MHz, CD3OD) δ ppm 0.19-0.26 (m,0.5H), 1.01-1.11 (m, 0.5H), 1.19-2.22 (m, 27H), 2.48-2.67 (m, 2H),2.76-3.23 (m, 2H), 3.44-3.78 (m, 4H), 3.90 (s, 1.5H), 3.92 (s, 1.5H),3.91-4.04 (m, 1.5H), 4.08-4.21 (m, 1.5H), 4.78-4.88 (m, 0.5H), 5.08 (d,J=15.0 Hz, 0.5H), 6.96-7.04 (m, 1H), 7.18 (d, J=2.6 Hz, 0.5H), 7.20 (d,J=2.2 Hz, 0.5H), 7.33 (d, J=8.4 Hz, 0.5H), 7.33 (d, J=8.8 Hz, 0.5H),7.59-7.73 (m, 0.5H), 7.70 (d, J=8.8 Hz, 0.5H), 7.78-7.88 (m, 0.5H), 7.87(d, J=8.8 Hz, 0.5H), 7.99 (s, 0.5H), 8.15 (br s, 0.5H). LC-MS retentiontime: 2.41 min; m/z 713 (MH−). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

Example 17

1a-((1-Acetyl-1,8-diazaspiro[4.5]dec-8-yl)carbonyl)-8-cyclohexyl-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.8-Cyclohexyl-1a-(1,8-diazaspiro[4.5]dec-8-ylcarbonyl)-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(16.3 mg, 0.024 mmol) and acetic acid (9 mg, 0.15 mmol) were dissolvedinto DMF (0.4 mL) and TEA (75 μL, 0.54 mmol) and stirred. HATU (19 mg,0.050 mmol) was added and the reaction mixture was stirred at rt for 1 h(complete by LCMS). The reaction mixture was diluted with MeOH, filteredand purified by preparative HPLC (CH₃CN/H₂O w/10 mM NH₄OAc) to yield1a-((1-acetyl-1,8-diazaspiro[4.5]dec-8-yl)carbonyl)-8-cyclohexyl-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(17 mg, 0.024 mmol, 98% yield) as an off-white solid. The compound wasisolated as a mixture of enantiomers and presents as a ˜1:1 mixture orrotamers or atrope isomers. ¹HNMR (300 MHz, CD₃OD) δ ppm 0.20-0.28 (m,0.5H), 1.02-1.14 (m, 3.5H), 1.19-2.29 (m, 24H), 2.48-2.67 (m, 2H),2.75-3.25 (m, 3H), 3.35-3.75 (m, 4H), 3.90 (s, 1.5H), 3.91 (s, 1.5H),4.08-4.29 (m, 1.5H), 4.35-4.59 (m, 0.5H), 4.78-4.88 (m, 0.5H), 5.07 (d,J=15.0 Hz, 0.5H), 6.95-7.03 (m, 1H), 7.17 (d, J=2.2 Hz, 0.5H), 7.19 (d,J=2.6 Hz, 0.5H), 7.32 (d, J=8.8 Hz, 0.5H), 7.32 (d, J=8.4 Hz, 0.5H),7.63-7.76 (m, 0.5H), 7.71 (d, J=8.8 Hz, 0.5H), 7.77-7.87 (m, 0.5H), 7.85(d, J=8.4 Hz, 0.5H), 8.02 (s, 0.5H), 8.18 (br s, 0.5H). LC-MS retentiontime: 2.39 min; m/z 713 (MH−). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 5% acetonitrile/95% H₂O/10 mMammonium acetate and solvent B was 5% H₂O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. Micromass Platform for LC in electrospray mode.

Example 18

8-Cyclohexyl-1a-(6,9-diazaspiro[4.5]undec-9-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.HATU (42 mg, 0.110 mmol) was added to a stirring solution of8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (50 mg, 0.091 mmol) and 6,9-diazaspiro[4.5]decane, 2HCl (42 mg,0.19 mmol) in DMF (0.5 mL) and TEA (150 μL, 1.076 mmol) and the reactionmixture was stirred at rt for 1 h (complete by LCMS). The reactionmixture was diluted with MeOH, filtered and purified by preparative HPLC(CH₃CN/H₂O w/10 mM NH₄OAc) in a single injection to yield8-cyclohexyl-1a-(6,9-diazaspiro[4.5]undec-9-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(31.2 mg, 0.046 mmol, 51% yield) as an off-white solid. LC-MS retentiontime: 2.31 min; m/z 671 (MH−). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 5% acetonitrile/95% H₂O/10 mMammonium acetate and solvent B was 5% H₂O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

Example 19

8-Cyclohexyl-1a-(1,4-diazaspiro[5.5]undec-4-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.HATU (42 mg, 0.110 mmol) was added to a stirring solution of8-cyclohexyl-5-((isopropylsulfonyl)carbamoyl)-11-methoxy-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (50 mg, 0.091 mmol) and 1,4-diazaspiro[5.5]undecane, HCl (42 mg,0.20 mmol) in DMF (0.5 mL) and TEA (150 μL, 1.076 mmol) and the reactionmixture was stirred at rt for 1 h (complete by LCMS). The reactionmixture was diluted with MeOH, filtered and purified by preparative HPLC(CH₃CN/H₂O w/10 mM NH₄OAc) in a single injection to yield8-cyclohexyl-1a-(1,4-diazaspiro[5.5]undec-4-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(48.2 mg, 0.070 mmol, 77% yield) as an off-white solid. LC-MS retentiontime: 2.39 min; m/z 685 (MH−). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 5% acetonitrile/95% H₂O/10 mMammonium acetate and solvent B was 5% H₂O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

Example 20

8-Cyclohexyl-1a-(6,9-diazaspiro[4.5]dec-9-ylcarbonyl)-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.HATU (42 mg, 0.110 mmol) was added to a stirring solution of8-cyclohexyl-11-methoxy-5-((propylsulfonyl)carbamoyl)-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (50 mg, 0.091 mmol) and 6,9-diazaspiro[4.5]decane, 2HCl (42 mg,0.20 mmol) in DMF (0.5 mL) and TEA (150 μL, 1.076 mmol) and the reactionmixture was stirred at rt for 1 h (complete by LCMS). The reactionmixture was diluted with MeOH, filtered and purified by preparative HPLC(CH₃CN/H₂O w/10 mM NH₄OAc) in a single injection to yield8-cyclohexyl-1a-(6,9-diazaspiro[4.5]dec-9-ylcarbonyl)-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(48.1 mg, 0.071 mmol, 79% yield) as an off-white solid. LC-MS retentiontime: 2.33 min; m/z 671 (MH−). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 5% acetonitrile/95% H₂O/10 mMammonium acetate and solvent B was 5% H₂O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

Example 21

8-Cyclohexyl-1a-(1,4-diazaspiro[5.5]undec-4-ylcarbonyl)-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.HATU (42 mg, 0.110 mmol) was added to a stirring solution of8-cyclohexyl-11-methoxy-5-((propylsulfonyl)carbamoyl)-1,12b-dihydrocyclopropa[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylicacid (50 mg, 0.091 mmol) and 1,4-diazaspiro[5.5]undecane, HCl (42 mg,0.19 mmol) in DMF (0.5 mL) and TEA (150 μL, 1.07 mmol) and the reactionmixture was stirred at rt for 1 h (complete by LCMS). The reactionmixture was diluted with MeOH, filtered and purified by preparative HPLC(CH₃CN/H₂O w/10 mM NH₄OAc) in a single injection to yield8-cyclohexyl-1a-(1,4-diazaspiro[5.5]undec-4-ylcarbonyl)-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(46.8 mg, 0.068 mmol, 75% yield) as an off-white solid. LC-MS retentiontime: 2.38 min; m/z 685 (MH−). LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 4 min, a hold time of 1 min, and ananalysis time of 5 min where solvent A was 5% acetonitrile/95% H₂O/10 mMammonium acetate and solvent B was 5% H₂O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

Example 22

1a-(6-Methyl-6,9-diazaspiro[4.5]undec-9-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.Sodium cyanoborohydride (15 mg, 0.24 mmol) was added to a stirringsolution of8-cyclohexyl-1a-(6,9-diazaspiro[4.5]undec-4-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(20 mg, 0.030 mmol) and formadehyde (100 μL, 1.23 mmol) indichloromethane (0.5 mL) and acetic acid (0.1 mL) and the reaction wasstirred 2 h. The reaction mixture was concentrated under a stream ofnitrogen overnight. The residue was dissolved into MeOH, filtered andpurified by preparitive HPLC (CH₃CN/H₂O with 10 uM NH₄OAc) in a singleinjection to yield1a-(6-methyl-6,9-diazaspiro[4.5]undec-9-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(16.8 mg, 0.024 mmol, 82% yield) as an off-white solid. The compound wasisolated as a mixture of enantiomers and presents as a 1:3 mixture ofrotamers or atrope isomers. ¹HNMR (300 MHz, CDCl₃) δ ppm 0.14-0.25 (m,0.25H), 0.42-3.09 (m, 33.75H), 3.31-3.55 (m, 1H), 3.59 (d, J=15.0 Hz,1H), 3.87 (s, 3H), 3.65-4.10 (m, 3H), 4.54-4.67 (m, 0.25H), 5.12 (d,J=15.0 Hz, 0.75H), 6.87-6.92 (m, 0.25H), 6.94 (dd, J=8.8, 2.6 Hz,0.75H), 7.00 (d, J=2.6 Hz, 0.25H), 7.08 (d, J=2.6 Hz, 0.75H), 7.20-7.29(m, 1H), 7.56 (br d, J=8.8 Hz, 0.25H), 7.66 (br d, J=8.4 Hz, 0.75H),7.84 (d, J=8.4 Hz, 0.25H), 7.86 (d, J=8.4 Hz, 0.75H), 7.97 (br s,0.25H), 8.01 (br s, 0.75H). LCMS retention time: 2.41 min; m/z 685(MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 5 mL/min, a gradient of 100%solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient timeof 4 min, a hold time of 1 min, and an analysis time of 5 min wheresolvent A was 5% acetonitrile/95% H₂O/10 mM ammonium acetate and solventB was 5% H₂O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.

Example 23

8-Cyclohexyl-1a-(1-methyl-1,4-diazaspiro[5.5]undec-4-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.Sodium cyanoborohydride (15 mg, 0.24 mmol) was added to a stirringsolution of8-cyclohexyl-1a-(1,4-diazaspiro[5.5]undec-4-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(17 mg, 0.025 mmol) and formadehyde (100 μL, 1.23 mmol) indichloromethane (0.5 mL) and acetic acid (0.1 mL) and the reaction wasstirred 2 h. The reaction mixture was concentrated under a stream ofnitrogen overnight. The residue was dissolved into MeOH, filtered andpurified by preparative HPLC (CH₃CN/H₂O with 10 uM NH₄OAc) in a singleinjection to yield8-cyclohexyl-1a-(1-methyl-1,4-diazaspiro[5.5]undec-4-ylcarbonyl)-N-(isopropylsulfonyl)-11-methoxy-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(16.0 mg, 0.023 mmol, 92% yield) as an off-white solid. The compound wasisolated as a racemic mixture and presents as a ˜1:5 mixture of rotamersor atrope isomers. Major isomer peaks reprted: ¹HNMR (300 MHz, CD₃OD) δ0.92-3.77 (m, 38H), 3.66 (d, J=15.4 Hz, 1H), 3.90 (s, 3H), 4.08-4.66 (m,1H), 5.14 (d, J=15.4 Hz, 1H), 7.03 (dd, J=8.4, 2.6 Hz, 1H), 7.19 (d,J=2.6 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.85 (d,J=8.8 Hz, 1H), 8.14 (s, 1H). LCMS retention time: 2.45 min; m/z 699(MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 5 mL/min, a gradient of 100%solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient timeof 4 min, a hold time of 1 min, and an analysis time of 5 min wheresolvent A was 5% acetonitrile/95% H₂O/10 mM ammonium acetate and solventB was 5% H₂O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.

Example 24

8-Cyclohexyl-1a-(6-methyl-6,9-diazaspiro[4.5]dec-9-ylcarbonyl)-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.Sodium cyanoborohydride (15 mg, 0.24 mmol) was added to a stirringsolution of8-cyclohexyl-1a-(6,9-diazaspiro[4.5]dec-9-ylcarbonyl)-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(17 mg, 0.025 mmol) and formadehyde (100 μL, 1.23 mmol) indichloromethane (0.5 mL) and acetic acid (0.1 mL) and the reaction wasstirred 2 h. The reaction mixture was concentrated under a stream ofnitrogen overnight. The residue was dissolved into MeOH, filtered andpurified by preparitive HPLC (CH₃CN/H₂O with 10 uM NH₄OAc) in a singleinjection to yield8-cyclohexyl-1a-(6-methyl-6,9-diazaspiro[4.5]dec-9-ylcarbonyl)-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(13.8 mg, 0.020 mmol, 80% yield) as an off-white solid. The compound wasisolated as a racemic mixture and presents as a ˜1:2 mixture of rotamersor atrope isomers. ¹HNMR (300 MHz, CD₃OD) δ 0.10-3.08 (m, 34H),4.31-4.13 (m, 5H), 3.86 (s, 3H), 4.41-4.61 (m, 0.33H), 5.04-5.16 (m,0.67H), 6.87 (dd, J=8.4, 2.2 Hz, 0.33H), 6.93 (dd, J=8.8, 2.6 Hz,0.67H), 7.00 (dd, J=2.2 Hz, 0.33H), 7.07 (dd, J=2.6 Hz, 0.67H),7.18-7.26 (m, 1H), 7.54-7.62 (m, 0.33H), 7.65 (d, J=8.4 Hz, 0.67H),7.75-7.83 (m, 0.33H), 7.84 (d, J=8.4 Hz, 0.67H), 7.97 (br s, 0.33H),8.01 (br s, 0.67H). LCMS retention time: 2.39 min; m/z 665 (MH−). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 mL/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, ahold time of 1 min, and an analysis time of 5 min where solvent A was 5%acetonitrile/95% H₂O/10 mM ammonium acetate and solvent B was 5% H₂O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

Example 25

8-Cyclohexyl-1a-(1-methyl-1,4-diazaspiro[5.5]undec-4-ylcarbonyl)-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide.Sodium cyanoborohydride (15 mg, 0.24 mmol) was added to a stirringsolution of8-cyclohexyl-1a-(1,4-diazaspiro[5.5]undec-4-ylcarbonyl)-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(15 mg, 0.022 mmol) and formaldehyde (100 μL, 1.23 mmol) indichloromethane (0.5 mL) and acetic acid (0.1 mL) and the reaction wasstirred 2 h. The reaction mixture was concentrated under a stream ofnitrogen overnight. The residue was dissolved into MeOH, filtered andpurified by preparitive HPLC (CH₃CN/H₂O with 10 uM NH₄OAc) in a singleinjection to yield8-cyclohexyl-1a-(1-methyl-1,4-diazaspiro[5.5]undec-4-ylcarbonyl)-11-methoxy-N-(propylsulfonyl)-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide(10.6 mg, 0.015 mmol, 69% yield) as an off-white solid. The compound wasisolated as a racemic mixture and presents as a ˜1:4 mixture of rotamersor atrope isomers. ¹HNMR (300 MHz, CD₃OD) δ 0.21-0.28 (m, 0.2H), 1.10(t, J=7.5 Hz, 3H), 0.98-3.75 (m, 31.8H), 3.66 (d, J=15.0 Hz, 1H), 3.90(s, 2.4H), 3.92 (s, 0.6H), 4.01-5.03 (m, 2.2H), 5.15 (d, J=15.0 Hz,0.8H), 6.95-7.02 (m, 0.2H), 7.02 (dd, J=8.4, 2.2 Hz, 0.8H), 7.19 (d,J=2.2 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.71-7.80 (m, 1H), 7.81-7.86 (m,1H), 8.15 (s, 0.8H), 8.20 (s, 0.2H). LCMS retention time: 2.42 min; m/z699 (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 mL/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 4 min, a hold time of 1 min, and an analysis time of 5 min wheresolvent A was 5% acetonitrile/95% H₂O/10 mM ammonium acetate and solventB was 5% H₂O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.

We claim:
 1. A compound of formula I

where: R¹ is CO₂R⁵ or CONR⁶R⁷; R² is a -5,5-, -5,6-, -5,7-, -6,6-,-6,7-, or -7,7- spirocyclic diamine attached to the carbonyl through onenitrogen and substituted with 0-3 R⁸ substituents; R³ is hydrogen, halo,alkyl, alkenyl, hydroxy, benzyloxy, or alkoxy; R⁴ is cycloalkyl; R⁵ ishydrogen or alkyl; R⁶ is hydrogen, alkyl, alkylSO₂, cycloalkylSO₂,haloalkylSO₂, (R⁹)(R¹⁰)NSO₂, or (R¹¹)SO₂; R⁷ is hydrogen or alkyl; R⁸ isoxo, hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, alkylcarbonyl,(cycloalkyl)carbonyl, alkoxycarbonyl, aminocarbonyl,(alkylamino)carbonyl, (dialkylamino)carbonyl, (R¹²)carbonyl, benzyl, orbenzyloxycarbonyl; R⁹ is hydrogen or alkyl; R¹⁰ is hydrogen or alkyl;R¹¹ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,N-(alkyl)piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, orhomomorpholinyl; and R¹² is azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, N-(alkyl)piperazinyl, morpholinyl, thiomorpholinyl,homopiperidinyl, or homomorpholinyl; or a pharmaceutically acceptablesalt thereof.
 2. A compound of claim 1 where R¹ is CONR⁶R⁷; R⁶ isalkylSO₂, cycloalkylSO₂, haloalkylSO₂, (R⁹)(R¹⁰)NSO₂, or (R¹¹)SO₂; andR⁷ is hydrogen.
 3. A compound of claim 1 where R³ is hydrogen.
 4. Acompound of claim 1 where R³ is methoxy.
 5. A compound of claim 1 whereR⁴ is cyclohexyl.
 6. A compound of claim 1 where R⁶ is (R⁹)(R¹⁰)NSO₂ or(R¹¹)SO₂.
 7. A compound of claim 1 according to the followingstereochemistry


8. A compound of claim 1 according to the following stereochemistry


9. A compound of claim 1 selected from the group consisting of

or a pharmaceutically acceptable salt thereof.
 10. A compositioncomprising a compound of claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 11. A method oftreating hepatitis C infection comprising administering atherapeutically effective amount of a compound of claim 1 to a patient.